Static cold storage (SCS) on ice has remained the gold standard preservation method for heart transplantation, and prolonged cold ischemia outside the typical 4–6 hour window is associated with an increased risk of primary graft dysfunction – a consequence attributed to ischemic damage and reperfusion injury. This, unfortunately limits the travel radius for donor heart procurement, a key factor that contributes to the overall shortage of donor organs. Recent research and clinical data have illustrated the validity of other preservation systems in preserving cardiac allografts, and many of these devices have shown promise in potentially prolonging the tolerated ischemic time beyond the accepted standard. Unfortunately, little is known regarding the biological basis of these preservation systems. In this review, we explore the existing knowledge of ischemic reperfusion injury as it relates to the donor heart. We also focus on characterizing the cellular and molecular mechanisms underlying existing donor heart preservation methods, including SCS, Paragonix’ SherpaPak, TransMedics’ Organ Care System, and XVIVO Heart Perfusion System, highlighting current limitations and areas for improvement. Furthermore, we describe the preclinical and clinical heart transplant outcomes related to Hypothermic Oxygenated Perfusate (HOPE) preservation.
PeledYDucharmeAKittlesonM, et al.International society for heart and lung transplantation guidelines for the evaluation and care of cardiac transplant candidates-2024. J Heart Lung Transplant2024; 43(10): 1529.e54–1628.e54.
2.
JacobSGargPWadiwalaI, et al.Strategies for expanding donors pool in heart transplantation. Rev Cardiovasc Med2022; 23(8): 285.
3.
BakhtiyarSSGodfreyELAhmedS, et al.Survival on the heart transplant waiting list. JAMA Cardiol2020; 5(11): 1227–1235.
4.
RoestSKaffka Genaamd DenglerSEvan SuylenV, et al.Waiting list mortality and the potential of donation after circulatory death heart transplantations in The Netherlands. Neth Heart J2021; 29(2): 88–97.
5.
DharmavaramNHessTJaegerH, et al.National trends in heart donor usage rates: are we efficiently transplanting more hearts?J Am Heart Assoc2021; 10(15): e019655.
6.
KilicAEmaniSSai-SudhakarCB, et al.Donor selection in heart transplantation. J Thorac Dis2014; 6(8): 1097–1104.
7.
SiddiqiHKSchlendorfKH. Hepatitis C positive organ donation in heart transplantation. Curr Transplant Rep2021; 8(4): 359–367.
8.
DeFilippisEMWaydaBLalaA, et al.Utilization of COVID-19 positive donors for Heart transplantation and associated short-term outcomes. J Heart Lung Transplant2023; 42(5): 651–659.
9.
HemmigeVSaeedOPuiusYA, et al.HIV D+/R+ heart/kidney transplantation: first case report. J Heart Lung Transplant2023; 42(3): 406–408.
10.
VellecaAShulloMADhitalK, et al.The International Society for Heart and Lung Transplantation (ISHLT) guidelines for the care of heart transplant recipients. J Heart Lung Transplant2023; 42(5): e1–e141.
11.
IyerAKumarasingheGHicksM, et al.Primary graft failure after heart transplantation. J Transplant2011; 2011: 175768.
12.
KaliyevRBekbossynovSNurmykhametovaZ. Sixteen-hour ex vivo donor heart perfusion during long-distance transportation for heart transplantation. Artif Organs2019; 43(3): 319–320.
13.
RegaFLebretonGParaM, et al.Hypothermic oxygenated perfusion of the donor heart in heart transplantation: the short-term outcome from a randomised, controlled, open-label, multicentre clinical trial. Lancet2024; 404(10453): 670–682.
14.
McGiffinDCKureCEMacdonaldPS, et al.Hypothermic oxygenated perfusion (HOPE) safely and effectively extends acceptable donor heart preservation times: results of the Australian and New Zealand trial. J Heart Lung Transplant2024; 43(3): 485–495.
15.
MoeslundNErtugrulIAHuMA, et al.Ex-situ oxygenated hypothermic machine perfusion in donation after circulatory death heart transplantation following either direct procurement or in-situ normothermic regional perfusion. J Heart Lung Transplant2023; 42(6): 730–740.
16.
BergKErtugrulISeefeldtJM, et al.Mitochondrial function after normothermic regional perfusion or direct procurement followed by hypothermic oxygenated machine perfusion in heart transplantation after circulatory death. Transplantation2025; 109(2): 300–308.
17.
LebretonGLeprinceP. Successful heart transplant after 12 h preservation aboard a commercial flight. Lancet2024; 403(10431): 1019.
18.
CopelandHHayangaJWANeyrinckA, et al.Donor heart and lung procurement: a consensus statement. J Heart Lung Transplant2020; 39(6): 501–517.
19.
KounatidisDBrozouVAnagnostopoulosD, et al.Donor heart preservation: current knowledge and the new era of machine perfusion. Int J Mol Sci2023; 24(23): 16693.
20.
SchmiadyMOGrafTOudaA, et al.An innovative cold storage system for donor heart transportation-lessons learned from the first experience in Switzerland. J Thorac Dis2021; 13(12): 6790–6799.
21.
MohitePNSefDUmakumarK, et al. Utilization of Paragonix SherpaPak for human donor heart preservation. Multimed Man Cardiothorac Surg. 2021; 2021.
22.
MichelSGLaMuraglia IiGMMadariagaML, et al.Innovative cold storage of donor organs using the Paragonix Sherpa Pak ™ devices. Heart Lung Vessel2015; 7(3): 246–255.
23.
LangmuurSJJAmeszJHVeenKM, et al.Normothermic ex situ heart perfusion with the organ care system for cardiac transplantation: a meta-analysis. Transplantation2022; 106(9): 1745–1753.
24.
Mendiola PlaMBerrettoniSLeeFH, et al.Video analysis of ex vivo beating hearts during preservation on the TransMedics® organ care system. Front Cardiovasc Med2023; 10: 1216917.
25.
EgleMLongnusSYildizM, et al. Surgical techniques for cardiac procurement, preparation and perfusion using the organ care system. Multimed Man Cardiothorac Surg. 2024; 2024. doi:10.1510/mmcts.2024.057.
26.
PradeganNGalloMFabozzoA, et al.Nonischemic donor heart preservation: new milestone in heart transplantation history. ASAIO J2023; 69(8): 725–733.
27.
WyssRKMéndez CarmonaNArnoldM, et al.Hypothermic, oxygenated perfusion (HOPE) provides cardioprotection via succinate oxidation prior to normothermic perfusion in a rat model of donation after circulatory death (DCD). Am J Transplant2021; 21(3): 1003–1011.
28.
WangLMacGowanGAAliS, et al.Ex situ heart perfusion: the past, the present, and the future. J Heart Lung Transplant2021; 40(1): 69–86.
29.
Van CaenegemOBeauloyeCVercruysseJ, et al.Hypothermic continuous machine perfusion improves metabolic preservation and functional recovery in heart grafts. Transpl Int2015; 28(2): 224–231.
30.
BrouckaertJDellgrenGWallinderA, et al.Non-ischaemic preservation of the donor heart in heart transplantation: protocol design and rationale for a randomised, controlled, multicentre clinical trial across eight European countries. BMJ Open2023; 13(12): e073729.
31.
BrouckaertJVandendriesscheKDegezelleK, et al.Successful clinical transplantation of hearts donated after circulatory death using direct procurement followed by hypothermic oxygenated perfusion: a report of the first 3 cases. J Heart Lung Transplant2024; 43(11): 1907–1910.
32.
NilssonJJernrydVQinG, et al.A nonrandomized open-label phase 2 trial of nonischemic heart preservation for human heart transplantation. Nat Commun2020; 11(1): 2976.
33.
See HoeLELi BassiGWildiK, et al.Donor heart ischemic time can be extended beyond 9 hours using hypothermic machine perfusion in sheep. J Heart Lung Transplant2023; 42(8): 1015–1029.
34.
MalhiHGoresGJ. Cellular and molecular mechanisms of liver injury. Gastroenterology2008; 134(6): 1641–1654.
35.
KahnJSchemmerP. Control of ischemia-reperfusion injury in liver transplantation: potentials for increasing the donor pool. Visc Med2018; 34(6): 444–448.
36.
KalogerisTBainesCPKrenzM, et al.Cell biology of ischemia/reperfusion injury. Int Rev Cell Mol Biol2012; 298: 229–317.
37.
ChouchaniETPellVRJamesAM, et al.A unifying mechanism for mitochondrial superoxide production during ischemia-reperfusion injury. Cell Metab2016; 23(2): 254–263.
38.
HatamiSQiXKhanM, et al.Oxidative stress and related metabolic alterations are induced in ex situ perfusion of donated hearts regardless of the ventricular load or leukocyte depletion. Am J Transplant2023; 23(4): 475–483.
39.
DutkowskiPGrafRClavienPA. Rescue of the cold preserved rat liver by hypothermic oxygenated machine perfusion. Am J Transplant2006; 6(5 Pt 1): 903–912.
40.
NakajimaDChenFYamadaT, et al.Hypothermic machine perfusion ameliorates ischemia-reperfusion injury in rat lungs from non-heart-beating donors. Transplantation2011; 92(8): 858–863.
41.
NakamuraMThouraniVHRonsonRS, et al.Glutathione reverses endothelial damage from peroxynitrite, the byproduct of nitric oxide degradation, in crystalloid cardioplegia. Circulation2000; 102(19 Suppl 3): III332–III338.
42.
WhiteCWAliAHasanallyD, et al.A cardioprotective preservation strategy employing ex vivo heart perfusion facilitates successful transplant of donor hearts after cardiocirculatory death. J Heart Lung Transplant2013; 32(7): 734–743.
43.
VervoornMTBallanEMvan TuijlS, et al.A Cardioprotective perfusion protocol limits myocardial functional decline during ex situ heart perfusion. JHLT Open2024; 3: 100042.
44.
JahaniaMSSanchezJANarayanP, et al.Heart preservation for transplantation: principles and strategies. Ann Thorac Surg1999; 68(5): 1983–1987.
SchlegelAMullerXMuellerM, et al.Hypothermic oxygenated perfusion protects from mitochondrial injury before liver transplantation. EBioMedicine2020; 60: 103014.
47.
AliAWangARibeiroRVP, et al.Static lung storage at 10°C maintains mitochondrial health and preserves donor organ function. Sci Transl Med2021; 13(611): eabf7601.
48.
MartinJLCostaASHGruszczykAV, et al.Succinate accumulation drives ischaemia-reperfusion injury during organ transplantation. Nat Metab2019; 1: 966–974.
49.
HorváthTJászDKBaráthB, et al.Mitochondrial consequences of organ preservation techniques during liver transplantation. Int J Mol Sci2021; 22(6): 2816.
50.
ChouchaniETPellVRGaudeE, et al.Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature2014; 515(7527): 431–435.
51.
LiCJacksonRM. Reactive species mechanisms of cellular hypoxia-reoxygenation injury. Am J Physiol Cell Physiol2002; 282(2): C227–C241.
52.
PiotCAWolfeCL. Apoptosis: a new mechanism of lethal myocardial “reperfusion injury”. J Thromb Thrombolysis1997; 4(1): 67–68.
53.
GottliebRABurlesonKOKlonerRA, et al.Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J Clin Investig1994; 94(4): 1621–1628.
54.
ZhaoZQVelezDAWangNP, et al.Progressively developed myocardial apoptotic cell death during late phase of reperfusion. Apoptosis2001; 6(4): 279–290.
55.
ZhaoZQVinten-JohansenJ. Myocardial apoptosis and ischemic preconditioning. Cardiovasc Res2002; 55(3): 438–455.
56.
HiguitaMLAjenuEOBolger-ChenM, et al. Alternative preservation strategies of DCD hearts: Effect of cold ischemia time before normothermic machine perfusion. medRxiv [Preprint]. 2025 Jun; 7: 2025.06.04.25329001. doi:10.1101/2025.06.04.25329001.
57.
SandhaJKWhiteCWMüllerA, et al.Steroids limit myocardial edema during ex vivo perfusion of hearts donated after circulatory death. Ann Thorac Surg2018; 105(6): 1763–1770.
58.
MichelSGLa MuragliaGMMadariagaML, et al.Preservation of donor hearts using hypothermic oxygenated perfusion. Ann Transplant2014; 19: 409–416.
59.
BessemsMDoorschodtBMHooijschuurO, et al.Optimization of a new preservation solution for machine perfusion of the liver: which is the preferred colloid?Transplant Proc2005; 37(1): 329–331.
60.
DrinkwaterDCRudisELaksH, et al.University of Wisconsin solution versus Stanford cardioplegic solution and the development of cardiac allograft vasculopathy. J Heart Lung Transplant1995; 14(5): 891–896.
61.
CrispSJDunnMJRoseML, et al.Antiendothelial antibodies after heart transplantation: the accelerating factor in transplant-associated coronary artery disease?J Heart Lung Transplant1994; 13(1 Pt 1): 81–91, ; discussion 91-2.
62.
DesroisMCausTBellesPM, et al.Nitric oxide pathway after long-term cold storage and reperfusion in a heterotopic rat heart transplantation model. Transplant Proc2005; 37(10): 4553–4555.
63.
QinGWohlfartBZuoL, et al.Intact coronary and myocardial functions after 24 hours of non-ischemic heart preservation. Scand Cardiovasc J2020; 54(1): 59–65.
64.
CompagnonPLevesqueEHentatiH, et al.An oxygenated and transportable machine perfusion system fully rescues liver grafts exposed to lethal ischemic damage in a pig model of DCD liver transplantation. Transplantation2017; 101(7): e205–e213.
65.
FalkCIusFRojas-HernandezSV, et al.Effects of ex vivo perfusion and il-6 receptor blockade on ischemia reperfusion injury in cardiac transplantation. J Heart Lung Transplant2019; 38(4): S240.
66.
Editorial Office. Erratum to machine perfusion of donor heart with normothermic blood versus hypothermic HTK in preserving coronary endothelium in a porcine model of DCD. Ann Palliat Med2021; 10(6): 7151–7152.
67.
SchroderJNPatelCBDeVoreAD, et al.Increasing utilization of extended criteria donor hearts for transplantation: the OCS heart EXPAND trial. JACC Heart Fail2024; 12(3): 438–447.
68.
ArdehaliAEsmailianFDengM, et al.Ex-vivo perfusion of donor hearts for human heart transplantation (PROCEED II): a prospective, open-label, multicentre, randomised non-inferiority trial. Lancet2015; 385(9987): 2577–2584.
69.
IsathAOhiraSLevineA, et al.Ex vivo heart perfusion for cardiac transplantation allowing for prolonged perfusion time and extension of distance traveled for procurement of donor hearts: an initial experience in the United States. Transplant Direct2023; 9(3): e1455.
70.
AlomariMGargPYazjiJH, et al.Is the organ care system (OCS) still the first choice with emerging new strategies for donation after circulatory death (DCD) in heart transplant?Cureus2022; 14(6): e26281.
71.
LeonM. Revolutionizing donor heart procurement: innovations and future directions for enhanced transplantation outcomes. J Cardiovasc Dev Dis2024; 11(8): 235.
72.
SteenSPaskeviciusALiaoQ, et al.Safe orthotopic transplantation of hearts harvested 24 hours after brain death and preserved for 24 hours. Scand Cardiovasc J2016; 50(3): 193–200.
73.
LänginMReichartBSteenS, et al.Cold non-ischemic heart preservation with continuous perfusion prevents early graft failure in orthotopic pig-to-baboon xenotransplantation. Xenotransplantation2021; 28(1): e12636.
74.
GriffithBPGoerlichCESinghAK, et al.Genetically modified porcine-to-human cardiac xenotransplantation. N Engl J Med2022; 387(1): 35–44.
