Intact coronary and myocardial functions after 24 hours of non-ischemic heart preservation

Qin, Guangqi; Wohlfart, Björn; Zuo, Li; Hu, Jingfeng; Sjöberg, Trygve; Steen, Stig

doi:10.1080/14017431.2019.1684553

Cited by 11 publications

(16 citation statements)

References 19 publications

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“…(d) High oncotic pressure in the preservation medium inhibits edema formation; strict pressure‐ and flow‐controlled coronary perfusion helps to reduce capillary damage and aggravation of myocardial edema. (e) Lastly, physiological levels of catecholamines, cortisol, and thyroid hormones are substituted in the solution to maintain myocardial energy stores and cardiac function after cold preservation 22,23 ; cocaine blocks the re‐uptake of catecholamines into the nerve terminals, thereby ensuring physiological concentrations around alpha‐ and beta‐receptors in the graft 13 …”

Section: Discussionmentioning

confidence: 99%

“…After transplantation all recipient pigs were stable with normal blood pressures without inotropic support, normal urine production, and normal blood gases, indicating adequate organ perfusion 12 . In another study using the same method of organ preservation, the porcine hearts kept normal coronary artery endothelium‐dependent relaxation and myocardial contractility without edema formation 13 . Very recently, a phase 2 trial demonstrated the feasibility and safety of non‐ischemic heart preservation in human heart transplantation 14 .…”

Section: Introductionmentioning

confidence: 94%

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Cold non‐ischemic heart preservation with continuous perfusion prevents early graft failure in orthotopic pig‐to‐baboon xenotransplantation

Längin

Reichart²,

Steen

et al. 2020

Xenotransplantation

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Background Successful preclinical transplantations of porcine hearts into baboon recipients are required before commencing clinical trials. Despite years of research, over half of the orthotopic cardiac xenografts were lost during the first 48 hours after transplantation, primarily caused by perioperative cardiac xenograft dysfunction (PCXD). To decrease the rate of PCXD, we adopted a preservation technique of cold non‐ischemic perfusion for our ongoing pig‐to‐baboon cardiac xenotransplantation project. Methods Fourteen orthotopic cardiac xenotransplantation experiments were carried out with genetically modified juvenile pigs (GGTA1‐ KO/hCD46/hTBM) as donors and captive‐bred baboons as recipients. Organ preservation was compared according to the two techniques applied: cold static ischemic cardioplegia (IC; n = 5) and cold non‐ischemic continuous perfusion (CP; n = 9) with an oxygenated albumin‐containing hyperoncotic cardioplegic solution containing nutrients, erythrocytes and hormones. Prior to surgery, we measured serum levels of preformed anti‐non‐Gal‐antibodies. During surgery, hemodynamic parameters were monitored with transpulmonary thermodilution. Central venous blood gas analyses were taken at regular intervals to estimate oxygen extraction, as well as lactate production. After surgery, we measured troponine T and serum parameters of the recipient’s kidney, liver and coagulation functions. Results In porcine grafts preserved with IC, we found significantly depressed systolic cardiac function after transplantation which did not recover despite increasing inotropic support. Postoperative oxygen extraction and lactate production were significantly increased. Troponin T, creatinine, aspartate aminotransferase levels were pathologically high, whereas prothrombin ratios were abnormally low. In three of five IC experiments, PCXD developed within 24 hours. By contrast, all nine hearts preserved with CP retained fully preserved systolic function, none showed any signs of PCXD. Oxygen extraction was within normal ranges; serum lactate as well as parameters of organ functions were only mildly elevated. Preformed anti‐non‐Gal‐antibodies were similar in recipients receiving grafts from either IC or CP preservation. Conclusions While standard ischemic cardioplegia solutions have been used with great success in human allotransplantation over many years, our data indicate that they are insufficient for preservation of porcine hearts transplanted into baboons: Ischemic storage caused severe impairment of cardiac function and decreased tissue oxygen supply, leading to multi‐organ failure in more than half of the xenotransplantation experiments. In contrast, cold non‐ischemic heart preservation with continuous perfusion reliably prevented early graft failure. Consistent survival in the perioperative phase is a prerequisite for preclinical long‐term results after cardiac xenotransplantation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

Cold non‐ischemic heart preservation with continuous perfusion prevents early graft failure in orthotopic pig‐to‐baboon xenotransplantation

Längin

Reichart²,

Steen

et al. 2020

Xenotransplantation

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“…During the first 6 months after transplantation, we also observed less ACR in the NIHP group than in the SCS group. Decreased allograft rejection may suggest that the endothelium was less damaged in the NIHP group; this has been demonstrated in preclinical studies, and is attributable to less ischemia/reperfusion injuries 8,15,22 . According to the latest International Society for Heart and Lung Transplantation registry report, treatment for rejection within the first year after transplantation was associated with an increased risk of CAV development and an increased mortality risk of up to 50% at 5 years 12 .…”

Section: Discussionmentioning

confidence: 78%

“…Preclinical studies, using the NIHP system, have shown that the pig donor heart can be safely preserved for 24 h and that the endothelium contractile function can be preserved for at least 8 h 8,13,15 . In a recently published study of life-supporting porcine cardiac xenotransplantation using the same system, NIHP was one of two keys to the success 16 .…”

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confidence: 99%

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

et al. 2020

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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-inhuman study shows the feasibility and safety of NIHP for clinical use in heart transplantation. ClinicalTrial.gov, number NCT03150147

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“…Among other factors, the combination of inadequate perfusion and lack of colloid in the perfusate might also have played a specific role. In pilot studies of porcine heart preserved using HMP, we observed that the albumin concentration in the perfusate was positively related to the myocardial water content ( 48 , 49 ). The feasibility and effectiveness of this method have been shown in a clinical study ( 6 ).…”

Section: Discussionmentioning

confidence: 98%

Machine Perfusion for Human Heart Preservation: A Systematic Review

et al. 2022

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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.

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Intact coronary and myocardial functions after 24 hours of non-ischemic heart preservation

Cited by 11 publications

References 19 publications

Cold non‐ischemic heart preservation with continuous perfusion prevents early graft failure in orthotopic pig‐to‐baboon xenotransplantation

Cold non‐ischemic heart preservation with continuous perfusion prevents early graft failure in orthotopic pig‐to‐baboon xenotransplantation

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

Machine Perfusion for Human Heart Preservation: A Systematic Review

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