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Cyclosporine A as a Cardioprotective Agent During Donor Heart Retrieval, Storage, or Transportation

Benefits and Limitations

Gao, Ling PhD1,*; Hicks, Mark PhD1,2,3,*; Villanueva, Jeanette E. PhD1,4; Doyle, Aoife MEngSc1; Chew, Hong C. MBBS1; Qui, Min Ru PhD5; Jabbour, Andrew PhD1,6,7; Dhital, Kumud K. FRACS, PhD1,6,7; Macdonald, Peter S. PhD, MD1,6,7

doi: 10.1097/TP.0000000000002629
Original Basic Science—General
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Background. Storage of donor hearts in cardioplegic solutions supplemented with conditioning agents activating endogenous mitochondrial protective signaling enhanced their postreperfusion recovery. The present study investigates the role of timing and duration of cardiac exposure to cyclosporine A (CsA), another putative mitochondrial protectant, on cardiac functional recovery and potential mechanisms of CsA action in an isolated working rat heart model of donor heart retrieval and storage.

Methods. After measurement of baseline function, hearts were arrested and stored for 6 hours at 4°C in either Celsior alone or Celsior + CsA (0.2 µM), then reperfused for 45 minutes in Krebs solution, when functional recovery was assessed. Two additional groups of Celsior-alone stored hearts were exposed to 0.2 µM CsA for the initial 15 minutes (nonworking period) or the full 45-minute period of reperfusion. Coronary effluent was collected pre- and poststorage for assessment of lactate dehydrogenase release. Tissue samples were collected at the end of each study for immunoblotting and histological studies.

Results. CsA supplementation during cold storage or the first 15-minute reperfusion significantly improved functional recovery and significantly increased phospho-AMPKαThr172 and phospho-ULK-1Ser757. Hearts exposed to CsA for 45 minutes at reperfusion recovered poorly with no phospho–AMP-activated protein kinase α activation, decreased phospho-eNOSSer633, and decreased mitochondrial cytochrome c content with increased lactate dehydrogenase release.

Conclusions. Inclusion of CsA during cold storage is cardioprotective. Effects of CsA addition to the perfusate during reperfusion were time dependent, with benefits at 15 minutes but not 45 minutes of reperfusion. The toxic effect with the presence of CsA for the full 45-minute reperfusion is associated with impaired mitochondrial integrity and decreased eNOS phosphorylation.

1 Cardiac Physiology and Transplantation, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.

2 Department of Clinical Pharmacology and Toxicology, St Vincent’s Hospital, Darlinghurst, NSW, Australia.

3 Department of Physiology and Pharmacology, University of New South Wales, Randwick, NSW, Australia.

4 St Vincent’s Clinical School, University of New South Wales, Randwick, NSW, Australia.

5 Department of Anatomical Pathology, SydPath, St Vincent’s Hospital, Darlinghurst, NSW, Australia.

6 Heart and Lung Transplant Unit, St Vincent’s Hospital, Darlinghurst, NSW, Australia.

7 Faculty of Medicine, University of New South Wales, Randwick, NSW, Australia.

Received 19 July 2018. Revision received 11 November 2018.

Accepted 29 November 2018.

* L.G. and M.H. are co-first authors.

L.G., M.H., J.E.V., A.D., H.C.C., M.R.Q., A.J., K.K.D., and P.S.M. participated in study design, writing of paper, performance of research, and data analysis.

The authors received funding from the National Health and Medical Research Council (program grant ID 1074386) and St Vincent’s Clinical Foundation of Australia to support work presented in this manuscript.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

Correspondence: Peter S. Macdonald, MBBS, PhD, MD, Heart Transplant Unit, St Vincent’s Hospital, Victoria St, Darlinghurst, NSW 2010, Australia. (peter.macdonald@svha.org.a).

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