Is There Hope With Hypothermic Oxygenated Perfusion?

Heart transplantation remains the most effective treatment for patients with advanced heart failure. However, the growing number of individuals awaiting transplantation continues to outpace the availability of donor hearts. A major limitation to the broader use of this lifesaving procedure is the restricted supply of suitable donor organs. Among recipients, primary graft dysfunction (PGD) remains the leading cause of early mortality, within the first 30 d posttransplant. Several factors associated with the standard transplant process, such as donor brain death, hypothermic and warm ischemia, and ischemia/reperfusion injury, are known contributors to the development of PGD.1 As a result, significant research efforts have focused on minimizing ischemic injury during ex vivo transport to improve graft viability and extend preservation windows. The current gold standard for ex vivo preservation is static cold storage (SCS), which involves placing the donor heart in a cardioplegic crystalloid solution, enclosed in a sterile bag and transported in an ice-filled container at approximately 4 °C.2 Based on this method, limiting total graft ischemic time to be within 4 h is associated with improved outcomes and reduced mortality.3,4 New technologies seek to optimize temperature control and preservation duration beyond the capabilities of traditional SCS. The SherpaPak system by Paragonix represents a refinement of cold storage by maintaining the heart in a nonperfused cardioplegic environment with more consistent temperature regulation between 4 and 8 °C, and the potential for up to 30 h of controlled storage.5 In contrast, the TransMedics Organ Care System uses normothermic perfusion, maintaining the donor heart in a beating, metabolically active state during transport.6 Hypothermic oxygenated perfusion (HOPE) offers a hybrid strategy, merging cold preservation with intermittent oxygenated perfusion to reduce ischemic injury.7 In the present study by Hoe et al, the authors expand on their prior work by evaluating 2- and 8-h HOPE preservation compared with the standard 2-h SCS protocol.8 They assess safety and efficacy in both brain-dead (BD) and non-BD (sham) donor models, focusing on posttransplant mitochondrial function, contractile response, and electrophysiologic performance. Physiologically, all transplanted hearts were successfully weaned from cardiopulmonary bypass (CPB), but notable differences in posttransplant viability emerged. Two of 8 BD hearts and 3 of 8 sham hearts preserved via SCS failed to support recipients posttransplant, a manifestation of PGD. In contrast, all 26 hearts preserved with HOPE supported recipients through the 6-h post-CPB study endpoint. Mitochondrial functional analysis in the left ventricle demonstrated significantly increased complex I–linked oxidative phosphorylation with both 2-and 8-h HOPE compared with SCS. Complex II-linked oxidative phosphorylation was significantly improved in the 8-h HOPE group. In addition, maximal noncoupled respiration was enhanced across HOPE groups, and mitochondrial membrane potential generation was significantly elevated in 2-h HOPE versus SCS-preserved hearts. These findings indicate improved mitochondrial bioenergetics with HOPE, particularly in the BD setting. BD hearts preserved by HOPE retained a contractile response to noradrenaline, whereas those preserved via 2-h SCS demonstrated reduced potency. Electrophysiologic outcomes also favored HOPE: SCS-preserved hearts exhibited more pronounced voltage attenuation, lower unipolar electrogram slew rates (dV/dt), prolonged endocardial activation times, and fewer detectable Purkinje potentials posttransplant. These findings suggest that SCS may contribute to conduction abnormalities and arrhythmogenic substrates, particularly in the setting of brain death. Importantly, this study highlights the added vulnerability of BD donor hearts and demonstrates that HOPE may mitigate both general and BD-specific injury mechanisms. Although long-term clinical outcome data in patients remain limited, the evidence thus far supports HOPE as a promising alternative to SCS, offering improved metabolic and functional preservation, especially in high-risk allografts. However, widespread adoption of advanced preservation technologies such as HOPE, SherpaPak, or Organ Care System must be weighed against cost, complexity, and logistical burden. These systems demand greater expertise in procurement and have not yet demonstrated clear long-term superiority in all settings.9,10 Further research is needed to determine optimal use cases and cost-effectiveness of these modalities and validate their uses clinically in terms of reductions in rates of PGD, improved 1 y and long-term survival. Furthermore, salutary effects on long-term outcomes in heart transplant recipients, such as a reduction in the incidence of cardiac allograft vasculopathy, may be a consequence of a reduction in the frequency of PGD from HOPE. Nonetheless, the data suggest a future in which dynamic or hybrid preservation approaches may become increasingly necessary not only to improve early graft function but also to expand geographic reach, acceptable donor pool, and optimize recipient center preparedness. HOPE shows strong potential (or hope) to address current limitations in donor preservation and should remain a focus of clinical investigation.