Pre-clinical heart transplantation studies have shown that ex vivo non-ischemic heart preservation (NIHP) can be safely used for 24 h. Here we perform a prospective, open-label, non-randomized phase II study comparing NIHP to static cold preservation (SCS), the current standard for adult heart transplantation. All adult recipients on waiting lists for heart transplantation were included in the study, unless they met any exclusion criteria. The same standard acceptance criteria for donor hearts were used in both study arms. NIHP was scheduled in advance based on availability of device and trained team members. The primary endpoint was a composite of survival free of severe primary graft dysfunction, free of ECMO use within 7 days, and free of acute cellular rejection ≥2R within 180 days. Secondary endpoints were I/R-tissue injury, immediate graft function, and adverse events. Of the 31 eligible patients, six were assigned to NIHP and 25 to SCS. The median preservation time was 223 min (IQR, 202–263) for NIHP and 194 min (IQR, 164–223) for SCS. Over the first six months, all of the patients assigned to NIHP achieved event-free survival, compared with 18 of those assigned to SCS (Kaplan-Meier estimate of event free survival 72.0% [95% CI 50.0–86.0%]). CK-MB assessed 6 ± 2 h after ending perfusion was 76 (IQR, 50–101) ng/mL for NIHP compared with 138 (IQR, 72–198) ng/mL for SCS. Four deaths within six months after transplantation and three cardiac-related adverse events were reported in the SCS group compared with no deaths or cardiac-related adverse events in the NIHP group. This first-in-human study shows the feasibility and safety of NIHP for clinical use in heart transplantation. ClinicalTrial.gov, number NCT03150147 Ischemia and reperfusion damage contribute to early graft dysfunction and recipient’s death. Here the authors show the feasibility and safety of a non-ischemic heart preservation method for heart transplantation in a non-randomized trial.

A nonrandomized open-label phase 2 trial of nonischemic heart preservation for human heart transplantation.

Currently, static cold storage (SCS) of hearts from donations after brainstem death remains the standard clinically. However, machine perfusion (MP) is considered an approach for donor organ management to extend the donor pool and/or increase the utilization rate. This review summarizes and critically assesses the available clinical data on MP in heart transplantation. We searched Medline (PubMed), Cochrane, Embase, and clinicaltrials.gov, along with reference lists of the included publications and identified 40 publications, including 18 articles, 17 conference abstracts, and five ongoing clinical trials. Two types of MP were used: hypothermic MP (HMP) and normothermic MP (NMP). Three studies evaluated HMP, and 32 evaluated NMP. Independent of the system, MP resulted in clinical outcomes comparable to traditional SCS. However, NMP seemed especially beneficial for high-risk cases and donation after circulatory death (DCD) hearts. Based on currently available data, MP is non-inferior to standard SCS. Additionally, single-centre studies suggest that NMP could preserve the hearts from donors outside standard acceptability criteria and DCD hearts with comparable results to SCS. Finally, HMP is theoretically safer and simpler to use than NMP. If a machine malfunction or user error occurs, NMP, which perfuses a beating heart, would have a narrower margin of safety. However, further well-designed studies need to be conducted to draw clear conclusions.

Machine Perfusion for Human Heart Preservation: A Systematic Review

BACKGROUND The aim of this study was to investigate the oxygen consumption of explanted aerobically-perfused cardioplegic porcine hearts at different temperatures. MATERIAL AND METHODS Explanted hearts from 30 pigs weighing 50 kg were randomized into 5 groups. The hearts received continuous antegrade perfusion within a temperature-controlled sealed system. The perfusate consisted of an albumin-containing hyperoncotic cardioplegic nutrition solution with erythrocytes to a hematocrit of 10%. Five temperatures were studied: 37, 30, 22, 15, and 8°C. When the erythrocytes in the perfusate were fully saturated, the oxygenator was excluded from the circuit and blood gases were analyzed periodically until the erythrocytes had desaturated to less than 20%. Between 80% and 60% saturation the desaturation curves were linear in all groups and the oxygen consumption was calculated from this part of the curves. RESULTS The weight of the hearts was 208±4 g (mean ±SEM, n=30). The oxygen consumption in mL/min/100 g heart tissue was (mean ±SEM, n=6 in each group) 37°C: 1.10±0.04; 30°C: 0.58±0.02; 22°C: 0.33±0.01; 15°C: 0.21±0.01; and 8°C: 0.16±0.02. CONCLUSIONS The oxygen consumption of the cardioplegic perfused pig heart at normothermia was 1.1 mL/min/100 g and was reduced by 85% to 0.16 mL/min/100 g at 8°C.

/pdf/oxygen-consumption-of-the-aerobically-perfused-cardioplegic-5so7tus21i.pdf

Oxygen Consumption of the Aerobically-Perfused Cardioplegic Donor Heart at Different Temperatures.

INTRODUCTION
To validate slaughterhouse hearts for ex-situ heart perfusion studies, we compared cold oxygenated machine perfusion in less expensive porcine slaughterhouse hearts (N = 7) to porcine hearts that are harvested following the golden standard in laboratory animals (N = 6).


METHODS
All hearts received modified St Thomas 2 crystalloid cardioplegia prior to 4 hours of cold oxygenated machine perfusion. Hearts were perfused with homemade modified Steen heart solution with a perfusion pressure of 20-25 mmHg to achieve a coronary flow between 100-200 mL/min. Reperfusion and testing was performed for 4 hours on a normothermic, oxygenated diluted whole blood loaded heart model. Survival was defined by a cardiac output above 3 L with a mean aortic pressure above 60 mmHg.


RESULTS
Both groups showed 100% functional survival, with laboratory hearts displaying superior cardiac function. Both groups showed similar decline in function over time.


CONCLUSION
We conclude that the slaughterhouse heart can be used as an alternative to laboratory hearts and provides a cost-effective method for future ex-situ heart perfusion studies.

https://journals.sagepub.com/doi/pdf/10.1177/02676591231152718

Validation of the slaughterhouse porcine heart model for ex-situ heart perfusion studies.

Primary graft dysfunction is an important cause of morbidity and mortality after cardiac transplantation. Donor brain stem death (BSD) is a significant contributor to donor heart dysfunction and primary graft dysfunction. There remain substantial gaps in the mechanistic understanding of peritransplant cardiac dysfunction. One of these gaps is cardiac metabolism and metabolic function. The healthy heart is an "omnivore," capable of utilizing multiple sources of nutrients to fuel its enormous energetic demand. When this fails, metabolic inflexibility leads to myocardial dysfunction. Data have hinted at metabolic disturbance in the BSD donor and subsequent heart transplantation; however, there is limited evidence demonstrating specific metabolic or mitochondrial dysfunction. This review will examine the literature surrounding cardiometabolic and mitochondrial function in the BSD donor, organ preservation, and subsequent cardiac transplantation. A more comprehensive understanding of this subject may then help to identify important cardioprotective strategies to improve the number and quality of donor hearts.

/pdf/peritransplant-cardiometabolic-and-mitochondrial-function-3seg564hj2.pdf

Peritransplant Cardiometabolic and Mitochondrial Function: The Missing Piece in Donor Heart Dysfunction and Graft Failure

Objectives. The aim of the study was to investigate if adequate preservation of coronary artery endothelium-dependent relaxation and contractility may be obtained after 8 hours of non-ischemic heart preservation. Design. Porcine hearts were perfused for 8 hours at 8 °C, either in cycles of 15 minutes perfusion and 60 minutes non-perfusion, or by continuous perfusion. The perfusate consisted of a cardioplegic, hyperoncotic nutrition solution with oxygenated red cells, and the perfusion pressure was 20 mmHg. In organ baths, coronary artery segments from the preserved hearts were studied and compared to fresh controls. Results. Endothelium-dependent relaxation and contractility were fully preserved after both intermittent and continuous perfusion, as compared to fresh controls. No myocardial edema was seen; water content of the myocardium was 79.5 ± 0.2%, 79.0 ± 0.4% and 79.0 ± 0.3% (ns) for fresh controls, intermittently perfused, and continuously perfused hearts, respectively. Conclusion. Intact endothelial and contractile function of coronary artery may be obtained after 8 hours of non-ischemic heart preservation. (Less)

/pdf/intact-endothelial-and-contractile-function-of-coronary-2bbiyqijj7.pdf

Intact endothelial and contractile function of coronary artery after 8 hours of heart preservation.

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Intact endothelial and contractile function of coronary artery after 8 hours of heart preservation.