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. Author manuscript; available in PMC: 2026 Mar 5.
Published in final edited form as: Perfusion. 2025 Sep 9;41(5):547–558. doi: 10.1177/02676591251377571

Understanding Donor Heart Preservation: Cellular Mechanisms and Clinical Outcomes

Morgan K Moroi 1,+, Yaagnik Kosuri 1,+, Sebastian Johannes Bauer 1,2, Anthony Campbell 1, Arianna Adamo 1,3, Cary Karcher 1, Brianna Costa 1, Claire Kho 1, Ephraim Jacobson 1, Shawn Lee 1, Payam Akhyari 2, Koji Takeda 1, Giovanni Ferrari 1,*
PMCID: PMC12958456  NIHMSID: NIHMS2144847  PMID: 40925572

Abstract

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, contributing 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 prolonging the tolerated ischemic time. 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 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.

Keywords: Heart transplantation, preservation, static cold storage, ischemic reperfusion injury, hypothermic oxygenated machine perfusion, Donor Heart preservation, cardiac surgery, organ preservation

INTRODUCTION

Heart transplantation remains the standard of care in the treatment of end-stage heart failure1. Despite the increasing number of annual heart transplants, the demand for donor organs far exceeds the supply. In 2023, around 5,000 heart transplants were performed worldwide, while nearly 50,000 patients remained waiting for a suitable organ2. Unfortunately, the mortality rate on the heart transplant waiting list remains high, with only 35% of patients on the waiting list surviving at 5 years3. There are several factors that contribute to the inadequate donor pool. First, heart preservation is limited by a maximum ischemic time of 4-6 hours of static cold storage (SCS). Additionally, even if the recipient is within an acceptable travel radius, donor hearts may be deemed unsuitable due to strict donor selection criteria or other medical, cultural, and ethical considerations2,4–6. Ultimately, fewer than 40% of donor hearts are eligible for donation5.

Efforts to expand the donor pool have been quite extensive in recent years, mostly focused on broadening the criteria for transplantable hearts and developing methods to safely extend the organ’s preservation time2. Transplantation of donor hearts from patients with hepatitis C virus (HCV), human immunodeficiency virus (HIV), or SARS-CoV-2 infection have been demonstrated to be successful7–9. Donation after circulatory death (DCD) and inclusion of opt-out donation policies have allowed for further expansion of the donor pool. While broadening the criteria for transplantable hearts has been implemented in some centers, all efforts remain limited by the ischemic damage that occurs during the ex vivo transport interval and subsequent reperfusion injury10. Increasing ischemic time beyond 4-6 hours has been shown to be associated with higher risks of impaired graft function, early graft failure, and subsequent higher post-transplant mortality11.

Technological advances in organ preservation have started to allow for the safe extension of ischemic time without increasing risk for primary graft dysfunction. Within the past decade, there has been significant interest in the development of ex vivo heart perfusion devices that utilize oxygenated and nutrient-enriched solutions to reduce ischemic reperfusion injury (IRI) and better preserve mechanical and metabolic cardiac function. Normothermic machine perfusion, which preserves the donor heart in a warm beating state, has demonstrated feasibility up to 16 hours of preservation with recovery of cardiac function following implantation12. However, this method requires two instances of ischemia and reperfusion during organ harvest and unloading the heart from the device for implantation into the recipient, potentially increasing the risk of myocardial damage. More recently, hypothermic oxygenated machine perfusion (HOPE) has emerged another preservation strategy with demonstrated success in clinical and preclinical heart transplant studies, with the longest clinical preservation time recorded at 12 hours13–17.

This review explores in detail the underlying cellular and molecular mechanisms related to static cold storage organ preservation and HOPE. Additionally, we describe the preclinical and clinical heart transplant outcomes related to HOPE preservation.

STANDARD STATIC COLD STORAGE PRESERVATION

SCS preservation is the most utilized method of heart preservation worldwide18 (Figure 1A). Typically, this procedure involves arresting the heart by cross-clamping the aorta and continuously infusing cold preservation solution through the coronary vasculature. Following standard cardiectomy, the donor heart is then placed in a sterile bag filled with preservation solution and transported in an ice cooler between 0-4°C19. While this hypothermia does not fully halt cellular metabolism, the metabolic rate decreases to approximately 10-12% of normothermic conditions, mitigating adverse effects of ischemia during transport19. Furthermore, it reduces the rate of lysis of organelles such as lysosomes, preventing release of autolytic enzymes and resultant cell death. Unfortunately, static cold storage remains an imperfect solution, as hypothermia is associated with some disadvantages including cell swelling, impaired Na/K ATPase activity, and cell membrane damage.

Figure 1.

Figure 1.

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Images of (A) static cold storage (SCS) and (B) Paragonix Sherpa Pak (Images courtesy of Paragonix Technologies, Inc. All rights reserved).

To combat the local ice injury related to standard SCS, there have been developments in storing cardiac grafts at slightly higher temperatures. Paragonyx (Paragonyx Technologies Inc., Braintree, MA, USA) has developed the SherpaPak system to safely transport donor hearts between 4-8°C, a range shown to reduce metabolic demand and hypoxic injury from ischemia, while avoiding cellular damage and protein denaturation that can occur at colder temperatures20 (Figure 1B). In the Paragonix SherpaPak® Cardiac Transport System, the heart is suspended in a temperature controlled cannister filled with cold cardioplegic preservation solution21. The cannister is placed in a cooler and surrounded by disposable cooling packs that change phase at 5°C to maintain the target preservation temperature range21. While in the cooler, the heart does not contact the walls of the cannister to avoid local ice-injury, as seen with standard SCS22. Although the system is designed for transport times of up to 4 hours, preclinical work has demonstrated the SherpaPak can maintain optimal temperature ranges for 30 hours, even in varying outer environmental temperatures22.

EX VIVO NORMOTHERMIC PERFUSION

In the past 5 years, groups have also examined ex vivo normothermic perfusion as a method to preserve donor hearts. For example, TransMedics (TransMedics Inc., Andover, MA, USA) developed the Organ Care System (OCS) Heart Device, which has demonstrated promising results in the maintenance of hearts that might have previously been unsuitable for procurement and transplant due to DCD conditions or marginal donor characteristics23 (Figure 2A, B). In 2022, the Food and Drug Administration (FDA) ultimately approved the preservation method that allows for ex vivo reanimation of hearts from DCD donors, further increasing the cardiac donor pool24. The TransMedics OCS™ Heart device consists of a reservoir, oxygenator, and centrifugal pump. Following cardioplegic arrest and explantation of the donor heart, an aortic cannula is inserted to perfuse the coronaries antegrade, and an additional cannula is placed in the pulmonary artery to collect the blood that returns from the coronary sinus. A third cannula is placed in the left atrium to vent the left ventricle and avoid distension before the heart is then connected to the closed circulatory system24,25. The perfusate is warm, oxygenated leukocyte-reduced donor blood enriched with a proprietary mix of electrolytes and nutrients. Once aortic flow is activated, the heart is closely monitored to ensure electrical activity resumes, and the inferior vena cava is tied off. External pacing and defibrillation may be used as needed to establish adequate rhythm. During normothermic reperfusion, the flow is titrated to a target range of 650-850 mL/min, as measured by return cannula in the pulmonary artery as a surrogate for coronary flow. Typically, the aortic root pressure is between 70-85 mmHg to achieve target coronary flows. Serial blood gases are assessed while the heart is loaded to monitor electrolytes, hematocrit, and lactate. With this method, cardiac allografts have been implanted after “out of body” times of up to 16 hours12. Through careful attempts at mimicking physiological conditions, the device has been associated wit reduction in ischemic injury and cellular damage as well as protein denaturation, all of which are often associated with prolonged SCS24.

Figure 2.

Figure 2.

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(A) Device image and (B) schematic of normothermic Transmedics Organ Care System.

HYPOTHERMIC OXYGENATED MACHINE PERFUSION (HOPE)

HOPE preservation involves preserving the heart in a hypothermic non-beating state by perfusing the organ with a nutrient-rich oxygenated solution mixed with red blood cells. Currently, the XVIVO Heart Perfusion System (XVIVO Systems, Sweden AB) is the only portable nonischemic HOPE heart preservation system used clinically for ground and airborne transportation of donor hearts (Figure 3A, B, C). From a technical perspective, the heart is easily loaded onto the device by placing an aortic cannula to provide antegrade perfusion of the coronaries with XVIVO Solution and a C-shaped silicone tube across the mitral valve to prevent left ventricular distention. Perfusion is initiated at 8°C, and the aortic root pressure is titrated to 20 mmHg. Maintaining the heart in this hypothermic state slows down metabolic processes at the cellular level, lowering energy consumption and ultimately reducing pro-apoptotic pathways26. By delivering an oxygenated solution with red blood cells, preclinical studies have shown that myocardial cells may be able to restore depleted ATP levels27–29. Overall, the device combines the benefits of hypothermia and oxygenated perfusion to consequently reduce graft dysfunction and the risk of ischemia-reperfusion injury30.

Figure 3.

Figure 3.

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(A) Aortic inflow cannula, (B) device image, and (C) schematic of hypothermic oxygenated XVIVO Heart Assist Transport system. Images courtesy of XVIVO Perfusion AB.

This device has demonstrated potential for safely and effectively extending donor heart ischemic times beyond the standard four hours14,17, and it has been utilized in donors following brain death (DBD) and circulatory death (DCD)31. Despite its promising results and advantages, the XVIVO Heart Perfusion System has not received FDA regulatory approval as of February 2024. However, clinical trials are ongoing.

CELLULAR MECHANISMS UNDERLYING CARDIAC ALLOGRAFT PRESERVATION

Although various heart preservation techniques have been successfully adopted clinically, there is limited research on the impact of these methods on the biomolecular profile of hearts32. The cell biology research of organ storage, particularly with respect to HOPE, has been largely dominated by studies on liver and lung; studies on the heart have been limited33. Here, we seek to consolidate evidence from prior animal studies for the impact of storage on known cellular pathways. In most cases, the evidence presented is shown in other organs; however, where available, we present data for heart preservation.

Oxidative Stress and Reactive Oxygen Species

During out-of-body ischemic time, decreased oxygen supply in the donor organ leads to the upregulation of anaerobic metabolism and decreased intracellular ATP. This causes a cascade of events in which ATP-dependent Na+/K+ and Ca2+ pumps fail causing abnormal intracellular Ca2+accumulation34–36. Calcium accumulation is the trigger for oxidative energy and mitochondrial electron transport chain disruption, which induces the production of abnormally high amounts of ROS, including superoxide anions, hydrogen peroxide, and hydroxyl radicals. The overproduction of ROS results in atypical cell signaling biomolecular damage, inflammation and apoptosis37. The return of oxygen to cardiac tissue during reperfusion also triggers the production of ROS through the hypoxanthine-xanthine oxidase reaction. Superoxide anions, hydrogen peroxide, hypochlorous acid, and hydroxyl radicals, contribute to cellular damage via lipid peroxidation, polymerization of mucopolysaccharides, and oxidation of protein sulfhydryl groups. Free radicals cause cross-linking of membrane proteins, cleave peptide bonds, modify glycosaminoglycan function, and induce DNA damage. Furthermore, tissue ischemia depletes antioxidants protective against reperfusion injury.

Little research exists on the role of ROS during the preservation of cardiac grafts. In ex situ normothermic machine perfusion, devices utilize leukocyte-reduced blood-based perfusate to reduce inflammation and oxidative stress in the heart while it is loaded on the device. Unfortunately, it is known that, despite this, ex situ normothermic machine perfusion is associated with oxidative stress, inflammation, and gradual myocardial functional decline with increasing preservation time38.

On the other hand, in liver studies, HOPE has been associated with a decrease in both oxidative stress and cell death following reperfusion after preservation, likely related to dampened pathways under hypothermic conditions39. Similarly, evidence from lung transplantation also suggests there may be reduced oxidative damage during reperfusion in HOPE recipients. Histological presence of 8-OHdG (a common marker for oxidative damage to DNA) was found in bronchial and alveolar epithelial cells and pulmonary arterial endothelial cells in the SCS group, suggesting increased oxidative damage compared to HOPE40.

Understanding the importance of mitigating oxidative stress and ROS during heart preservation, prior studies have explored adding exogenous antioxidants to preservation solutions to limit reperfusion injury. For example, glutathione has been shown to limit oxidative damage by scavenging free radicals and reactive oxygen species41. Some groups have explored cardioprotective reperfusion strategies to reduce ROS-production during ex vivo normothermic machine perfusion preservation42,43. Some HOPE preservation fluids have also previously incorporated other antioxidants and free radical scavengers, such as superoxide dismutase, allopurinol, prostaglandin synthesis inhibitors, and vitamin E44.

It Is worth noting that the production of ROS Is not entirely harmful to cellular function, as Its balance with antioxidants is essential for maintaining cellular homeostasis. For example, ROS is necessary for inducing reversible post-translational protein modifications45.

Mitochondrial Function and Metabolic Processes

Evidence from lung and liver storage methods suggests that mitochondrial function and damage are directly related to organ longevity and overall outcomes after transplantation, and that mitochondrial health and viability might be improved in HOPE preservation as compared to SCS16,46–48. During ischemic conditions the cell switches from aerobic to anaerobic energy production, reversing the action of succinate dehydrogenase (SDH) in the citric acid cycle, leading to succinate accumulation49, a proxy for mitochondrial damage and health48,50. Furthermore, during reperfusion, the influx of oxygen can open the mitochondrial permeability transition pore, causing mitochondrial swelling, cessation of mitochondrial functions (i.e. energy production (ATP)), and the release of cytochrome C. This process activates proapoptotic pathways and results in various cell death forms, including apoptosis, necrosis, and autophagy51–55.

Experimentation in liver tissue has demonstrated that both succinate accumulation and flavin mononucleotide (FMN) release by the mitochondria are decreased in HOPE preserved grafts when compared to SCS and a normothermic preservation technique46. It has also been demonstrated in rat liver that FMN release from Complex I is significantly decreased during HOPE storage when compared to preservation under normothermic conditions39.

Furthermore, studies involving rat hearts demonstrated that 30 minutes of treatment with HOPE led to better cardiac outcomes and lower succinate accumulation27. In another study, porcine hearts were procured under DCD conditions followed by either 60 minutes of NRP and subsequent 3 hours of HOPE or only 3 hours of HOPE prior to transplantation. Mitochondrial viability was measured before storage, after a preservation, and after transplantation. NADH-linked respiration, oxidative phosphorylation, and coupling efficiency gradually declined throughout the process without a significant difference between the two groups. The decline of oxidative phosphorylation was further associated with higher levels of troponin, suggesting a correlation between mitochondrial dysfunction and cardiomyocyte damage. While this does not demonstrate the superiority of HOPE preservation, it suggests that HOPE may be at least equivalent to NRP when it comes to mitochondrial preservation16. Further studies are needed to assess the impact of ischemic reperfusion injury on mitochondrial health after HOPE preservation.

Regarding ex vivo normothermic machine perfusion, there is some evidence that mitochondrial dysfunction can be reversed during normothermic preservation. Ajenu et al. examined four human hearts from DCD donors that were rejected for transplant56. After extended time under cold storage, the hearts were loaded onto a normothermic machine perfusion device providing pulsatile flow for 6 hours at 37°C and then assessed real-time using resonance Raman spectroscopy (RRS) to quantify the mitochondrial redox state as a proxy for heart viability. Ajenu and colleagues reported that hearts with extended cold storage times exhibit larger ratios of reduced mitochondria and that normothermic preservation can reverse some of the myocardial dysfunction. RRS technology was also shown to be an effective assessment tool, as RRS was able to predict hearts with higher left ventricular function based upon mitochondrial function.

Cellular and Interstitial Edema

Intracellular and interstitial edema are common sequelae of heart preservation. Under normal physiologic conditions, cells are surrounded by an extracellular environment with a high concentration of sodium and a low concentration of potassium. The Na-K ATPase pump actively maintains this balance by expelling sodium from the cell and bringing in potassium, utilizing ATP generated through oxidative phosphorylation in the mitochondria. However, during anaerobic-hypothermic preservation, the suppression of the Na-K ATPase pump leads to a decline in membrane potential, resulting in sodium and chloride moving into the cell down their concentration gradients. This leads to a hyperosmolar intracellular environment, causing cellular swelling as water moves into the cell. To counteract this, preservation solutions frequently contain colloids that simulate intracellular osmotic pressure, preventing excessive water accumulation. In addition, impermeants – such as saccharides (glucose, mannitol) and anions (citrate, phosphate, sulfate, gluconate) – can help regulate osmotic balance and prevent intracellular edema.

Beyond cellular swelling, heart preservation can also be associated with interstitial edema. This condition is thought to arise when there is excessive hydrostatic pressure during the flushing process with cardioplegia solution. In a compounding fashion, extracellular edema can collapse capillaries within the tissue, further impeding perfusion and possibly leading to poor distribution of the preservation solution. As a mitigation strategy, colloids are incorporated into the preservation solutions to help generate colloidal oncotic pressure in the heart’s vasculature to limit interstitial fluid accumulation.

Ex vivo normothermic machine perfusion has also been associated with edema throughout the preservation time. In addition to the mechanisms previously described, it is believed that exposure to the extracorporeal circuit also triggers a proinflammatory response, similar to the process of systemic inflammation during cardiopulmonary bypass, and that this inflammatory response may be related to the development of myocardial edema57. In an effort to combat edema, methylprednisolone has been introduced in some normothermic perfusion systems in preclinical porcine studies, as a way to limit myocardial edema related to the proinflammatory response57.

Organ weight gain and edema have also been commonly reported following HOPE preservation. Michel and colleagues demonstrated more weight gain following 4 hours of HOPE (10.1% versus 1.1% increase compared to baseline, p<0.001), suggesting that machine perfusion may lead to some myocardial edema58. This weight gain was confirmed by the presence of edema on hematoxylin and eosin staining of myocardial tissue. However, it is important to note that, following 1 hour of reperfusion on the modified Langendorff system, HOPE and SCS hearts experienced similar weight gain (26.7 versus 29.9% increase compared to baseline). Other organs have reported weight gain during HOPE. In a study examining HOPE preservation of rat livers for 24 hours followed by 1 hour of normothermic reperfusion, liver grafts demonstrated significant weight gain during preservation, and the amount of weight gain was found to be dependent on the type of preservation solution used during HOPE59.

Endothelial Damage

Endothelial cells are particularly vulnerable to ischemic conditions. Several factors contribute to endothelial damage, including hypothermia, elevated intracellular calcium levels, and elevated intravascular potassium levels from cardioplegia delivery60,61. Under normal physiologic conditions, the endothelium plays a key role in vascular homeostasis by releasing nitric oxide (NO), prostacyclin, and endothelium-derived hyperpolarizing factor – all of which target vascular smooth muscle to regulate vascular tone and permeability. During ischemia, these regulatory pathways become disrupted. Nitric oxide synthases become upregulated, leading to a reduction in NO production and impairment in endothelial function62. Endothelial integrity is also affected during ischemia, as endothelial cells are unable to uphold the stability of the endothelial barrier under ischemic conditions. Disruption of the barrier then triggers endothelial activation, resulting in the expression of proinflammatory cytokines, chemokines, and other molecules responsible for platelet adhesion and leukocyte recruitment. These processes can then cause microvascular obstructions, leading to a “no-reflow” phenomenon whereby ischemic myocardium is unable to be adequately reperfused following implantation of the donor organ, causing persistent ischemic damage.

Given the critical role of the endothelium in ensuring adequate blood delivery to the myocardium following reperfusion, preserving endothelial function during the organ preservation period may be as important as maintaining myocardial integrity. There are limited data surrounding outcomes of the endothelium in donor organs utilizing HOPE or normothermic machine perfusion. Steen and colleagues reported intact coronary endothelium dependent relaxation following 24 hours of HOPE preservation in a porcine model63. Further, in a study by Michel et al. investigated porcine hearts stored via HOPE versus SCS, HOPE hearts demonstrated decreased levels of endothelin-1 (ET-1, a marker for endothelial dysfunction) after 4 hours of preservation58. In addition, SCS hearts demonstrated endothelial cell rupture on scanning electron microscopy, while the integrity of the endothelial barrier in HOPE hearts was preserved. Similar findings regarding endothelial preservation have been reported in porcine liver studies examining HOPE preservation versus SCS64. Normothermic ex vivo preservation has been shown to reduce ischemic reperfusion injury at the endothelial level following transplantation65. In a study by Zhou et al., normothermic machine perfusion with autologous blood was associated with significantly decreased coronary endothelial dysfunction through inhibition of apoptosis and nitro-oxidative stress in the coronary arteries when compared to hypothermic machine perfusion with histidine-tryptophan-ketoglutarate (HTK) solution66. Some groups have also investigated the addition of cardioprotective mechanisms to normothermic machine perfusion. For example, methylprednisolone has been shown to demonstrate success in preserving endothelial cell integrity in a porcine preclinical model57.

PRECLINICAL AND CLINICAL OUTCOMES OF EX VIVO NORMOTHERMIC PERFUSION

Since its first application in HTx, the TransMedics OCS™ Heart device has had a significant impact in combating donor organ shortage. Especially as it was first introduced as a device for prolonged transport times, but is now also used in the context of marginal donors and DCD67. The first prospective randomized trial comparing TransMedics OCS™ to SCS (PROCEED II) was published in 2015 and showed no significant difference in short-term outcomes after HTx68, validating the safety of the system. The prospective, multi-center single-arm EXPAND trial further investigated the effectiveness of OCS in extended donor criteria. Donor hearts were included in the study if the expected ischemic time was more than 4 hours or if it was more than two hours in addition to other risk factors, such as older donor age or reduced left ventricular ejection fraction. A total of 173 hearts were assessed in the study, 150 were seen as eligible for HTx. Severe primary heart graft dysfunction (PGD) occurred in 6.7%. Patient survival was 93% and 86% at 6 and 24 months respectively, validating the effectiveness and safety of OCS in extended criteria donor hearts67. These results are further supported in a retrospective analysis by Isath et al. and a meta analysis by Langmuur et al, who both compared OCS to SCS23,69. Although transport time was significantly longer in patients undergoing HTx with OCS, SCS and OCS showed comparable results regarding PGD. Langmuur et al. additionally showed in 741 patients that when compared to SCS-DBD, there is no significant difference in early postoperative results when OCS is used in the setting of DCD23,26.

With prolonged ischemic time, a donor heart can potentially travel longer distances, meeting the needs of the expanding pool of recipients. However, it is worth mentioning that OCS comes at an additional cost for the procurement: $40,000-$80,000 per use70. Additionally, OCS is technically not as simple as SCS. Transportation logistics as well as the device itself are more complex and potentially require a bigger, more experienced procurement team. Regarding organ quality, higher risks of edema is suspected in longer preservation times when compared to HOPE71. In summary, the TransMedics OCS™ Heart device is the only FDA approved machine perfusion device for donor hearts, and this has already revolutionized the world of heart transplantation. It has been evaluated in DBD and DCD trials, providing satisfactory safety and efficacy results. Yet, complexity, manpower, and high costs may prevent smaller programs from its establishment.

PRECLINICAL AND CLINICAL OUTCOMES OF HYPOTHERMIC OXYGENATED MACHINE PERFUSION (HOPE)

Preclinical studies using HOPE have demonstrated animal heart grafts can be preserved for extended periods as well as in the context of DCD33,72. Steen et al. assessed hearts from a porcine DBD model that underwent 24 hours of HOPE preservation followed by transplantations72. Twenty-four hours after transplantation, adrenaline testing revealed hearts were still able to achieve an adequate increase in blood pressure and heart rate, validating the feasibility of the storage method72. Similarly, See Hoe et al. suggested that preservation time may be safely extended in an ovine heart transplant model33. Hearts preserved for 8 hours of HOPE perfusion were shown to demonstrate adequate contractile function, and HOPE recipients required less inotropic support, showed less vasoplegia, and exhibited lower lactate levels. Additionally, there was no significant cardiac damage by troponin release or histological analysis. The group also observed reduced inflammation in the HOPE group, as there was less neutrophilic infiltration and lower interleukin-6 (IL-6) levels post-transplant33. Moeslund et al. further investigated HOPE in the setting of a DCD model, comparing HOPE with and without normothermic regional perfusion (NRP) to SCS with NRP15. Hearts were preserved for 180 minutes and followed for 120 minutes post-transplant. Recipients transplanted with HOPE hearts showed increased biventricular contractility while receiving less inotropic support. Moreover, troponin levels were higher in the SCS group when compared to both NRP with and without NRP, suggesting less myocardial damage15.

In 2017, Nilsson et al. was the first to show the safety and feasibility of HOPE in human heart transplantation32. This first in-human study used the XVIVO device in six patients and showed no deaths or cardiac-related adverse events within a follow-up time of six months32. Outcomes were superior to the SCS arm (n = 25), in which four patients died and three patients suffered from cardiac-related serious adverse events. Although half of the HOPE patients (n = 3) experienced acute renal failure requiring continuous renal replacement therapy, all of them had fully recovered by the 6-month follow-up.

These results were emphasized by The Australian and New Zealand trial – a nonrandomized, single arm, multicenter trial assessing HOPE, involving preservation times of up to 6-8 hours14. A total of 36 patients were enrolled and then further subdivided into short and long preservation groups. One patient in each subgroup developed primary graft dysfunction. The mean and longest preservation time were 6 hours and 54 minutes and 8 hours and 47 minutes, respectively. McGiffin et al. observed a survival rate of 100% at 30 days, validating the feasibility and safety of HOPE in human hearts with preservation times beyond the usual 4-6 hours14. Additionally, a case report shows the feasibility of transatlantic organ transport with an ischemic time of >12 hours17.

The first patient in a HOPE randomized, controlled, multicenter clinical trial with a one year follow-up was enrolled in November 2020 in Europe30. Patients undergoing heart transplant were either allocated to conventional SCS or HOPE using XVIVO. Donor hearts could only be included in case of DBD, donor age of 18-70, and no known history of previous sternotomy. As of May 2023, 229 patients had been enrolled, and preliminary results were published in August 202413. A time to first event analysis within the first 30 days after transplant was conducted, and endpoints included cardiac-related death, moderate or severe PGD of the left or right ventricle, acute cellular rejection, or graft failure with the need for mechanical circulatory support or re-transplantation13. Fifty patients met the primary endpoint, involving 19 patients in the HOPE arm and 31 in the SCS arm. Utilization of XVIVO resulted in a risk reduction of 44%. Although not significantly different (p = 0.059), the study suggests a clinical benefit for HOPE. One year follow-up results in 2026 will give further information13.

Besides the recent success in allogenic heart transplant following DBD, HOPE has also shown promise in DCD scenarios31. In addition, it has shown encouraging results in the field of xenotransplantation73, as it was used in the first porcine-to-human xenotransplantation in 202274. However, in both allogenic and xenotransplantation, underlying cellular mechanisms have not been fully supported by biochemical and mechanistic evidence. Thus, further research is needed to characterize the biological processes underlying donor heart preservation and these various heart preservation methods. By investigating the cellular and biochemical pathways involved in these preservation techniques, evidence to explain variations in preservation times, primary graft dysfunction, heart injury, and overall success rates among different preservation models may be uncovered, ultimately allowing for the advancement of preservation techniques and patient outcomes.

CONCLUSION

Ex vivo machine perfusion holds significant clinical promise for the preservation of donor hearts during heart transplantation. Clinical trials have suggested that organ preservation time can be safely extended beyond the conventional 4-6 hours and therefore may allow for further expansion of the heart donor pool. However, much remains to be studied regarding the biochemical and metabolic pathways that underlay the preservation method. While preliminary studies in the lung and liver suggest normothermic machine perfusion and HOPE may mitigate cellular damage incurred during conventional organ preservation, there is a lack of knowledge about these biochemical processes in heart tissue, especially as they relate to cardiomyocyte health and long-term vitality. Further studies are warranted to better understand the heart’s biochemical and cellular response to current heart preservation techniques.

FUNDING STATEMENT

National Heart, Lung and Blood Institute of the National Institutes of Health (R01 HL 163085) to [GF], Research Agreement with xVIVO Perfusion Inc. [GF]. German Heart Foundation (Deutsche Herzstiftung e.V.) to [SJB].

ABBREVIATIONS

DBD

Donation after brain death

DCD

Donation after circulatory death

HOPE

Hypothermic Oxygenated Machine Perfusion

IL

Interleukin

IRI

Ischemic reperfusion injury

HOPE

Nonischemic heart-preservation

NRP

Normothermic regional perfusion

OCS

Organ care system

PGD

Primary graft dysfunction

SCS

Static cold storage

Footnotes

Disclosures

Research Agreement with xVIVO Perfusion Inc. [GF].

National Heart, Lung and Blood Institute, NIH (R01 HL 170573 and R01 HL 163085) [GF], The Kibel Fund for Aortic Valve Research [GF], T32HL007343 [YK], T32HL007854 [MM]

Andrew Sabin Family Foundation Cardiovascular Research Laboratory [GF)

CONFLICTS OF INTEREST

The authors do not have a financial interest or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this publication. Columbia Univeristy has a Research Agreeemtn with xVIVO Perfusion Inc.

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