Hypothermic oxygenated perfusion of the donor heart in heart transplantation: the short-term outcome from a randomised, controlled, open-label, multicentre clinical trial.

BACKGROUND: Static cold storage (SCS) remains the gold standard for preserving donor hearts before transplantation but is associated with ischaemia, anaerobic metabolism, and organ injuries, leading to patient morbidity and mortality. We aimed to evaluate whether continuous, hypothermic oxygenated machine perfusion (HOPE) of the donor heart is safe and superior compared with SCS. METHODS: We performed a multinational, multicentre, randomised, controlled, open-label clinical trial with a superiority design at 15 transplant centres across eight European countries. Adult candidates for heart transplantation were eligible and randomly assigned in a 1:1 ratio. Donor inclusion criteria were age 18-70 years with no previous sternotomy and donation after brain death. In the treatment group, the preservation protocol involved the use of a portable machine perfusion system ensuring HOPE of the resting donor heart. The donor hearts in the control group underwent ischaemic SCS according to standard practices. The primary outcome was time to first event of a composite of either cardiac-related death, moderate or severe primary graft dysfunction (PGD) of the left ventricle, PGD of the right ventricle, acute cellular rejection at least grade 2R, or graft failure (with use of mechanical circulatory support or re-transplantation) within 30 days after transplantation. We included all patients who were randomly assigned, fulfilled inclusion and exclusion criteria, and received a transplant in the primary analysis and all patients who were randomly assigned and received a transplant in the safety analyses. This trial was registered with ClicalTrials.gov (NCT03991923) and is ongoing. FINDINGS: A total of 229 patients were enrolled between Nov 25, 2020, and May 19, 2023. The primary analysis population included 204 patients who received a transplant. There were no patients who received a transplant lost to follow-up. All 100 donor hearts preserved with HOPE were transplantable after perfusion. The primary endpoint was registered in 19 (19%) of 101 patients in the HOPE group and 31 (30%) of 103 patients in the SCS group, corresponding to a risk reduction of 44% (hazard ratio 0·56; 95% CI 0·32-0·99; log-rank test p=0·059). PGD was the primary outcome event in 11 (11%) patients in the HOPE group and 29 (28%) in the SCS group (risk ratio 0·39; 95% CI 0·20-0·73). In the HOPE group, 63 (65%) patients had a reported serious adverse event (158 events) versus 87 (70%; 222 events) in the SCS group. Major adverse cardiac transplant events were reported in 18 (18%) and 33 (32%) patients in the HOPE and SCS group (risk ratio 0·56; 95% CI 0·34-0·92). INTERPRETATION: Although there was not a significant difference in the primary endpoint, the 44% risk reduction associated with HOPE was suggested to be a clinically meaningful benefit. Post-transplant complications, measured as major adverse cardiac transplant events, were reduced. Analysis of secondary outcomes suggested that HOPE was beneficial in reducing primary graft dysfunction. HOPE in donor heart preservation addresses the existing challenges associated with graft preservation and the increasing complexity of donors and heart transplantation recipients. Future investigation will help to further elucidate the benefit of HOPE. FUNDING: XVIVO Perfusion.

Innovations in transplant techniques for complex anomalies.

PURPOSE OF REVIEW: With advances in the field of congenital cardiac surgery and in the management of congenital heart defects in early life, the population of adult congenital heart disease (ACHD) patients is increasing. End-stage heart failure is currently the main cause of cardiovascular mortality and is expected to increase in the coming years. This review summarizes recent innovations in transplant techniques, with special attention to what is known in the population of ACHD recipients. RECENT FINDINGS: The use of machine perfusion for heart preservation enables longer preservation times. Normothermic (organ care system - OCS) and hypothermic (hypothermic oxygenated perfusion - HOPE) machine perfusion will alleviate the time pressure associated with heart transplantation in the ACHD population, may allow for expansion of the geographical range in which donors can be matched and may improve graft quality. Donation after circulatory death (DCD) heart transplantation, either through direct procurement-machine perfusion (DP-MP) or thoraco-abdominal normothermic regional perfusion (TA-NRP) is a viable strategy to further expand the donor pool. SUMMARY: The use of machine perfusion and DCD donors in ACHD is feasible and shows promise. Time pressure and shortage of donors is even more critical in ACHD than in other patient populations, making these innovations particularly relevant. Further clinical experience and research is needed to elucidate their impact.

The role of transesophageal echocardiography in guiding heart donation after circulatory death.

Heart donation after circulatory death (DCD) can significantly expand the heart donor pool, helping to overcome the problem of organ shortage and the increase in waiting list mortality and morbidity. To improve the outcome of DCD heart transplantation, thoraco-abdominal normothermic regional perfusion (TA-NRP) can be performed by selectively restoring circulation followed by in vivo functional heart assessment. Here, we report on the use of periprocedural transoesophageal echocardiography (TOE) as a minimally invasive cardiac assessment tool during different stages of a DCD heart procurement procedure using TA-NRP. We conclude that TOE is a valuable method to assess the donor heart for transplantation eligibility before and after withdrawal of life-sustaining therapy and during subsequent TA-NRP.

Oxygenated machine perfusion at room temperature as an alternative for static cold storage in porcine donor hearts.

BACKGROUND: There is a continued interest in ex situ heart perfusion as an alternative strategy for donor heart preservation. We hypothesize that oxygenated machine perfusion of donor hearts at a temperature that avoids both normothermia and deep hypothermia offers adequate and safe preservation. METHODS: Cardioplegia-arrested porcine donor hearts were randomly assigned to six hours of preservation using cold storage (CS, n = 5) or machine perfusion using an oxygenated acellular perfusate at 21°C (MP, n = 5). Subsequently, all grafts were evaluated using the Langendorff method for 120 min. Metabolic parameters and histology were analyzed. Systolic function was assessed by contractility and elastance. Diastolic function was assessed by lusitropy and stiffness. RESULTS: For both groups, in vivo baseline and post-Langendorff biopsies were comparable, as were lactate difference and myocardial oxygen consumption. Injury markers gradually increased and were comparable. Significant weight gain was seen in MP (p = 0.008). Diastolic function was not impaired in MP, and lusitropy was superior from 30 min up to 90 min of reperfusion. Contractility was superior in MP during the first hour of evaluation. CONCLUSION: We conclude that the initial functional outcome of MP-preserved hearts was transiently superior compared to CS, with no histological injury post-Langendorff. Our machine perfusion strategy could offer feasible and safe storage of hearts prior to transplantation. Future studies are warranted for further optimization.

A systematic review and meta-analyses of regional perfusion in donation after circulatory death solid organ transplantation.

In donation after circulatory death (DCD), (thoraco)abdominal regional perfusion (RP) restores circulation to a region of the body following death declaration. We systematically reviewed outcomes of solid organ transplantation after RP by searching PubMed, Embase, and Cochrane libraries. Eighty-eight articles reporting on outcomes of liver, kidney, pancreas, heart, and lung transplants or donor/organ utilization were identified. Meta-analyses were conducted when possible. Methodological quality was assessed using National Institutes of Health (NIH)-scoring tools. Case reports (13/88), case series (44/88), retrospective cohort studies (35/88), retrospective matched cohort studies (5/88), and case-control studies (2/88) were identified, with overall fair quality. As blood viscosity and rheology change below 20 °C, studies were grouped as hypothermic (HRP, ≤20 °C) or normothermic (NRP, >20 °C) regional perfusion. Data demonstrate that RP is a safe alternative to in situ cold preservation (ISP) in uncontrolled and controlled DCDs. The scarce HRP data are from before 2005. NRP appears to reduce post-transplant complications, especially biliary complications in controlled DCD livers, compared with ISP. Comparisons for kidney and pancreas with ISP are needed but there is no evidence that NRP is detrimental. Additional data on NRP in thoracic organs are needed. Whether RP increases donor or organ utilization needs further research.

Development of a computational simulator of the extracorporeal membrane oxygenation and its validation with in vitro measurements.

In the recent years, the use of extracorporeal membrane oxygenation (ECMO) has grown substantially, posing the need of having specialized medical and paramedical personnel dedicated to it. Optimization of the therapy, definition of new therapeutic strategies, and ECMO interaction with the cardiorespiratory system require numerous specific skills and preclinical models for patient successful management. The aim of the present work is to develop and validate a computational model of ECMO and connect it to an already existing lumped parameter model of the cardiorespiratory system. The ECMO model was connected between the right atrium and the aorta of the cardiorespiratory simulator. It includes a hydraulic module that is a representation of the tubing, oxygenator, and pump. The resulting pressures and flows within the ECMO circuit were compared to the measurements conducted in vitro on a real ECMO. Additionally, the hemodynamic effects the ECMO model elicited on the cardiorespiratory simulator were compared with experimental data taken from the literature. The comparison between the hydraulic module and the in vitro measurements evidenced a good agreement in terms of flow, pressure drops across the pump, across the oxygenator and the tubing (maximal percentage error recorded was 17.6%). The hemodynamic effects of the ECMO model on the cardiovascular system were in agreement with what observed experimentally in terms of cardiac output, systemic pressure, pulmonary arterial pressure, and left atrial pressure. The ECMO model we developed and embedded into the cardiorespiratory simulator, is a useful tool for the investigation of basic physiological mechanisms and principles of ECMO therapy. The model was sided by a user interface dedicated to training applications. As such, the resulting simulator can be used for the education of students, medical and paramedical personnel.

Implementation of a beating heart system for training in off-pump and minimally invasive coronary artery bypass.

BACKGROUND: Several training devices have been developed to train anastomotic skills in off-pump coronary artery bypass grafting (OPCAB). However, assessment of trainees' improvement remains challenging. The goal of this study was to develop a new practical scoring chart and investigate its reliability and utility for anastomotic skills in OPCAB and minimally invasive direct coronary artery bypass (MIDCAB). METHODS: A training device was used, which included a beating heart model installed in a dedicated box. A soft plastic tube was used as the left anterior descending artery, and a porcine ureter was used as the left internal mammary artery. Five cardiac surgery fellows (Fellows, > 5 year of surgical experience) and five residents or medical students (Residents, ≤ 5 year of surgical experience) were enrolled for this study. Before and after training, skills were evaluated using a scoring chart that took into account anastomotic time, leakage, shape, flow measurement, and self-estimation. RESULTS: Mean total score of all trainees was 15.4 ± 4.0 at pre-training and 18.5 ± 2.4 at post-training (P = 0.05). Before training, there was a significant difference in the total score between Fellows and Residents (18.6 ± 2.2 vs 12.2 ± 2.4 points, P = 0.002), which disappeared after training (19.4 ± 2.5 vs 17.6 ± 2.2 points, P = 0.262). Residents benefitted from training with improvements in their time, total score, score for time, score for flow and subtraction score; however, these effects were not seen in Fellows. The most evident training effect was improvement of self-estimation, which was also seen in Fellows. CONCLUSIONS: Residents were most likely to derive benefit from these training models with regard to both efficiency and quality. Training models seem to have an important role in making surgeons feel more comfortable with the procedure.

Bacterial cellulose as a promising material for pulmonary valve prostheses: In vivo study in a sheep model.

OBJECTIVES: Currently, no consensus exists regarding the most durable prosthesis for pulmonary valve replacement. Bacterial cellulose is a resistant, nonbiodegradable, nonpyrogenic bioimplant with low hemolysis and clotting properties. We hypothesized that bacterial cellulose heart valve prostheses could be an attractive alternative for pulmonary valve replacement. METHODS: We conducted a large animal model experiment in three adult sheep. The animals underwent open-heart surgery and cardiopulmonary bypass for bacterial cellulose conduit implantation in the pulmonary position. The sheep were followed for seven months, and clinical and laboratory parameters were analyzed. Echocardiographic evaluations were performed at 3 and 7 months. After seven months, the sheep were sacrificed and an autopsy was performed. The explanted conduits were radiologically and histopathologically analyzed. RESULTS: All sheep survived the operation, showing good recovery and normal health status; no adverse events were noted during the 7-month postoperative follow-up. Interval laboratory findings were normal with no signs of hemolysis or infection. Echocardiographic analysis after 7 months revealed a normal mean pressure gradient with excellent cusp motion and coaptation; a trace of regurgitation was found in two sheep. X-ray analysis of the explanted conduits revealed no structural defects in the leaflets with minimal calcification. Histological examination showed slight thickening of the conduit by pannus formation. No material failure, no calcification inside the material, and only minor calcification extrinsic to the matrix were observed. CONCLUSIONS: This pilot study provides evidence that bacterial cellulose may be suitable for pulmonary valve prostheses and surgical pulmonary artery plasty. Further studies on the high pressure side of the left heart are needed.

Reversal of Right Ventricular Remodeling After Correction of Pulmonary Regurgitation in Tetralogy of Fallot.

In the sheep model with pathophysiologic changes similar to patients with repaired TOF, severe PR leads to fibrotic changes in the RV. Pulmonary valve replacement reverses these fibrotic changes. Early valve replacement led to a quick RV recovery, and in time there was no difference in outcome between early and late valve replacement. These data support the benefit of valve replacement for RV function and suggest that there is a margin in the timing of the surgery. The fibrotic changes correlated well with the circulating biomarker PICP, which can have an added value in the clinical follow-up of patients with repaired TOF.

The international experience of in-situ recovery of the DCD heart: a multicentre retrospective observational study.

Background: Heart transplantation is an effective treatment offering the best recovery in both quality and quantity of life in those affected by refractory, severe heart failure. However, transplantation is limited by donor organ availability. The reintroduction of heart donation after the circulatory determination of death (DCD) in 2014 offered an uplift in transplant activity by 30%. Thoraco-abdominal normothermic regional perfusion (taNRP) enables in-situ reperfusion of the DCD heart. The objective of this paper is to assess the clinical outcomes of DCD donor hearts recovered and transplanted from donors undergoing taNRP. Method: This was a multicentre retrospective observational study. Outcomes included functional warm ischaemic time, use of mechanical support immediately following transplantation, perioperative and long-term actuarial survival and incidence of acute rejection requiring treatment. 157 taNRP DCD heart transplants, performed between February 2, 2015, and July 29, 2022, have been included from 15 major transplant centres worldwide including the UK, Spain, the USA and Belgium. 673 donations after the neurological determination of death (DBD) heart transplantations from the same centres were used as a comparison group for survival. Findings: taNRP resulted in a 23% increase in heart transplantation activity. Survival was similar in the taNRP group when compared to DBD. 30-day survival was 96.8% ([92.5%-98.6%] 95% CI, n = 156), 1-year survival was 93.2% ([87.7%-96.3%] 95% CI, n = 72) and 5-year survival was 84.3% ([69.6%-92.2%] 95% CI, n = 13). Interpretation: Our study suggests that taNRP provides a significant boost to heart transplantation activity. The survival rates of taNRP are comparable to those obtained for DBD transplantation in this study. The similar survival may in part be related to a short warm ischaemic time or through a possible selection bias of younger donors, this being an uncontrolled observational study. Therefore, our study suggests that taNRP offers an effective method of organ preservation and procurement. This early success of the technique warrants further investigation and use. Funding: None of the authors have a financial relationship with a commercial entity that has an interest in the subject.

Transplantation of donor hearts after circulatory death using normothermic regional perfusion and cold storage preservation.

OBJECTIVES: Hearts donated after circulatory determination of death are usually preserved with normothermic machine perfusion prior to transplantation. This type of preservation is costly, requires bench time adding to warm ischaemia, and does not provide a reliable evaluation of the unloaded donor heart. We report on 4 successful donation after circulatory death (category III) hearts transplanted after thoraco-abdominal normothermic regional perfusion (NRP) and static cold storage. METHODS: After life sustaining therapy was withdrawn and death was declared, perfusion to thoraco-abdominal organs was restored using extracorporeal circulation via cannulas in the femoral artery and vein and clamping of supra-aortic vessels. After weaning from extracorporeal circulation, cardiac function was assessed. Once approved, the heart was retrieved and stored using classic static cold storage. Data are expressed as median [min-max]. RESULTS: Donor and recipient ages were 44 years [12-60] (n = 4) and 53 years [14-64] (n = 4), respectively. Time from the withdrawal of life sustaining therapy to start of NRP was 22 min [18-31]. Cold storage time was 72 min [35-129]. Thirty-day survival was 100% with a left ventricle ejection fraction of 60% [50-60]. CONCLUSIONS: Donation after circulatory death heart transplantation using thoraco-abdominal NRP and subsequent cold storage preservation for up to 129 min was safe for 4 procedures and could be a way to expand the donor heart pool while avoiding costs of machine preservation.

Mechano-biological adaptation of the pulmonary artery exposed to systemic conditions.

Cardiac surgeries may expose pulmonary arterial tissue to systemic conditions, potentially resulting in failure of that tissue. Our goal was to quantitatively assess pulmonary artery adaptation due to changes in mechanical environment. In 17 sheep, we placed a pulmonary autograft in aortic position, with or without macroporous mesh reinforcement. It was exposed to systemic conditions for 6 months. All sheep underwent 3 ECG-gated MRI's. Explanted tissue was subjected to mechanical and histological analysis. Results showed progressive dilatation of the unreinforced autograft, while reinforced autografts stabilized after two months. Some unreinforced pulmonary autograft samples displayed more aorta-like mechanical behavior with increased collagen deposition. The mechanical behavior of reinforced autografts was dominated by the mesh. The decrease in media thickness and loss of vascular smooth muscle cells was more pronounced in reinforced than in unreinforced autografts. In conclusion, altering the mechanical environment of a pulmonary artery causes changes in its mechano-biological properties.

First report of a successful pediatric heart transplantation from donation after circulatory death with distant procurement using normothermic regional perfusion and cold storage.

Heart transplantation (HT) from donation after circulatory death (DCD) is a promising alternative to expand the heart donor pool. Cold storage can be used in a strategy to successfully retrieve and transplant DCD hearts after reconditioning using normothermic regional perfusion for distant procurement. Herein, we present the first report of a pediatric DCD heart reconditioned with normothermic regional perfusion, preserved using only cold storage while being transported to a neighboring center, and then successfully transplanted after nearly 2 hours of cold static storage. If supported by an appropriate trial, this finding could obviate the need to use expensive perfusion devices for short interhospital distances for DCD heart transportation and stimulate more centers across the world to embrace DCD HT.

The Effect of Dumping on Weight Loss in Conversion of Failed Restrictive Surgery: a Cross-Sectional Pilot Study.

PURPOSE: Dumping is currently seen as a negative side effect of Roux-en-Y gastric bypass (RYGB). However, it may help patients to comply with their prescribed diet. In this study, we assess the role of dumping on weight loss in patients who have undergone conversion of failed restrictive surgery into RYGB. METHODS: An analysis was performed of 100 consecutive patients who underwent revisional RYGB (rRYGB) between 2006 and 2011 due to inadequate weight loss or band intolerance after laparoscopic adjustable gastric banding (LAGB). The percentage of excess weight loss (%EWL) was used to evaluate weight reduction. The Sigstad clinical diagnostic index was used to detect dumping symptoms. RESULTS: Fifty-five patients (59.1%) suffered from dumping. Overall, dumpers showed a greater %EWL than non-dumpers (83.8 ± 48.0 vs 66.9 ± 44.1%, respectively, p = 0.0725). When rRYGB was performed because of inadequate weight loss following LAGB, dumping played a crucial role in weight loss (88.0 ± 21.2 vs 68.9 ± 34.5%, p = 0.0137). This effect positively correlates to post-LAGB body mass index (BMI) with a statistically significant result at BMI > 35 kg/m2 (82.4 ± 15.7 vs 58.4 ± 32.4%, p = 0.00341). A regression analysis of the Sigstad dumping score and %EWL shows that dumping tends to increase the %EWL. CONCLUSIONS: This study provides new insights into the effect of dumping on weight loss in patients who underwent conversion of failed restrictive surgery into RYGB. Based on the findings in our patient group, we suggest that dumping helps patients achieve sustainable weight loss. Therefore, dumping can be regarded as a positive side effect rather than a complication.

Moderating the Enthusiasm of Sleeve Gastrectomy: Up to Fifty Percent of Reflux Symptoms After Ten Years in a Consecutive Series of One Hundred Laparoscopic Sleeve Gastrectomies.

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) has become a popular one-stage bariatric procedure with a proven efficacy on weight loss. However, the relationship between LSG and gastroesophageal reflux disease (GERD) remains a subject of debate. The objective is to determine the long-term effect of LSG on weight loss and reflux disease. METHODS: A retrospective analysis of 100 consecutive patients who underwent an LSG between January 2005 and March 2009 was performed. The effect of LSG on weight evolution and the relationship between preoperative and postoperative GERD symptoms and PPI dependency was analyzed. RESULTS: A mean follow-up of 8.48 years (range 6.1-10.3) was achieved. We observed a long-term % excess weight loss (%EWL) of 60%. A significant increase in reflux symptoms and use of PPIs was seen. Seventeen percent suffered from reflux disease preoperatively versus 50% at the end of the postoperative follow-up (RR = 2.5882, 95% CI [1.6161-4.1452], p value = 0.0001). The chance of developing de novo reflux after LSG was 47.8% (32/67). Reflux disease was present in 7 of the 26 patients who underwent a secondary Roux-en-Y gastric bypass (RYGB). In four of these seven patients, reflux disease disappeared completely after the secondary RYGB (57.1%). CONCLUSIONS: A satisfactory long-term effect on weight loss was achieved. However, a significant increase in GERD and PPI dependency after LSG was noted. New onset GERD was seen in more than 40% of the study population. Conversion to RYGB is a good option in patients with refractory reflux disease after LSG.