Relation of body mass index to long-term survival and cardiac remodelling for patients undergoing mitral valve replacement surgery.

BACKGROUND AND AIMS: Studies have demonstrated that obesity is paradoxically associated with reduced mortality following cardiac surgery. However, these studies have treated various types of cardiac surgery as a single entity. With mitral valve (MV) surgeries being the fastest-growing cardiac surgical interventions in North America, the purpose of this study was to identify the impact of body mass index (BMI) on long-term survival and cardiac remodelling of patients undergoing MV replacement (MVR). METHODS AND RESULTS: In this retrospective, single-center study, 1071 adult patients who underwent an MVR between 2004 and 2018 were stratified into five BMI groups (<20, 20-24.9, 25-29.9, 30-34.9, >35). Cox proportional hazard regression models were used to determine the association between BMI and all-cause mortality. Patients who were underweight had significantly higher all-cause mortality rates at the longest follow-up (median 8.2 years) than patients with normal weight (p = 0.01). Patients who were in the obese group had significantly higher readmission rates due to myocardial infarction (MI) at the longest follow-up (p = 0.017). Subgroup analysis revealed a significant increase in long-term all-cause mortality for female patients who were underweight. Significant changes in left atrial size, mitral valve peak and mean gradients were seen in all BMI groups. CONCLUSIONS: For patients undergoing mitral valve replacement, BMI is unrelated to operative outcomes except for patients who are underweight.

The Effects of Oxygen-Derived Free-Radical Scavengers During Normothermic Ex-Situ Heart Perfusion.

Oxidative stress occurs during ex-situ heart perfusion (ESHP) and may negatively affect functional preservation of the heart. We sought to assess the status of key antioxidant enzymes during ESHP, and the effects of augmenting these antioxidants on the attenuation of oxidative stress and improvement of myocardial and endothelial preservation in ESHP. Porcine hearts were perfused for 6 hours with oxygen-derived free-radical scavengers polyethylene glycol (PEG)-catalase or PEG-superoxide dismutase (SOD) or with naive perfusate (control). The oxidative stress-related modifications were determined in the myocardium and coronary vasculature, and contractile function, injury, and endothelial integrity were compared between the groups. The activity of key antioxidant enzymes decreased and adding catalase and SOD restored the enzyme activity. Cardiac function and endothelial integrity were preserved better with restored catalase activity. Catalase and SOD both decreased myocardial injury and catalase reduced ROS production and oxidative modification of proteins in the myocardium and coronary vasculature. The activity of antioxidant enzymes decrease in ESHP. Catalase may improve the preservation of cardiac function and endothelial integrity during ESHP. While catalase and SOD may both exert cardioprotective effects, unbalanced SOD and catalase activity may paradoxically increase the production of reactive species during ESHP.

Cyclosporine A Does Not Mitigate Liver Ischemia/Reperfusion Injury in an Ex Vivo Porcine Model of Donation After Circulatory Death.

BACKGROUND Ischemia/reperfusion injury (IRI) is an inherent problem in organ transplantation, owing to the obligate period of ischemia that organs must endure. Cyclosporine A (CsA), though better know as an immunosuppressant, has been shown to mitigate warm IRI in a variety of organ types, including the liver. However, there is little evidence for CsA in preventing hepatic IRI in the transplant setting. MATERIAL AND METHODS In the present study, we tested the effect of CsA on hepatic IRI in a large-animal ex vivo model of donation after circulatory death (DCD). Porcine donors were pre-treated with either normal saline control or 20 mg/kg of CsA. Animals were subject to either 45 or 60 minutes of warm ischemia before hepatectomy, followed by 2 or 4 hours of cold storage prior to reperfusion on an ex vivo circuit. Over the course of a 12-hour perfusion, perfusion parameters were recorded and perfusate samples and biopsies were taken at regular intervals. RESULTS Peak perfusate lactate dehydrogenase was significantly decreased in the lower-ischemia group treated with CsA compared to the untreated group (4220 U/L [3515-5815] vs 11 305 [10 100-11 674]; P=0.023). However, no difference was seen between controls and CsA-treated groups on other parameters in perfusate alanine or asparagine aminotransferase (P=0.912, 0.455, respectively). Correspondingly, we found no difference on midpoint histological injury score (P=0.271). CONCLUSIONS We found minimal evidence that CsA is protective against hepatic IRI in our DCD model.

Effect of red blood cell storage time in pediatric cardiac surgery patients: A subgroup analysis of a randomized controlled trial.

Objective: This study aimed to determine whether or not transfusion of fresh red blood cells (RBCs) reduced the incidence of new or progressive multiple organ dysfunction syndrome compared with standard-issue RBCs in pediatric patients undergoing cardiac surgery. Methods: Preplanned secondary analysis of the Age of Blood in Children in Pediatric Intensive Care Unit study, an international randomized controlled trial. This study included children enrolled in the Age of Blood in Children in Pediatric Intensive Care Unit trial and admitted to a pediatric intensive care unit after cardiac surgery with cardiopulmonary bypass. Patients were randomized to receive either fresh (stored ≤7 days) or standard-issue RBCs. The primary outcome measure was new or progressive multiple organ dysfunction syndrome, measured up to 28 days postrandomization or at pediatric intensive care unit discharge, or death. Results: One hundred seventy-eight patients (median age, 0.6 years; interquartile range, 0.3-2.6 years) were included with 89 patients randomized to the fresh RBCs group (median length of storage, 5 days; interquartile range, 4-6 days) and 89 to the standard-issue RBCs group (median length of storage, 18 days; interquartile range, 13-22 days). There were no statistically significant differences in new or progressive multiple organ dysfunction syndrome between fresh (43 out of 89 [48.3%]) and standard-issue RBCs groups (38 out of 88 [43.2%]), with a relative risk of 1.12 (95% CI, 0.81 to 1.54; P = .49) and an unadjusted absolute risk difference of 5.1% (95% CI, -9.5% to 19.8%; P = .49). Conclusions: In neonates and children undergoing cardiac surgery with cardiopulmonary bypass, the use of fresh RBCs did not reduce the incidence of new or progressive multiple organ dysfunction syndrome compared with the standard-issue RBCs. A larger trial is needed to confirm these results.

The Impact of Ex Situ Heart Perfusion in Pediatric Transplantation: An Analysis of the OPTN Database.

Ex situ heart perfusion (ESHP) has increased the pool of donors in adults. However, this is not true in pediatrics due to lack of devices. Therefore, we sought to understand organ refusal in pediatrics and estimate donor heart usage with ESHP. Donor hearts offered to pediatrics were identified from the Organ Procurement and Transplantation Network Database (2000-2019). A linear regression model was built to predict average travel speed, and the extended maximum permitted distance with ESHP was calculated. This extended distance was compared with the policy for maximum travel distance. There were 33,708 donor offers (n = 10,807 hearts) to pediatric programs [24.1% (n = 2,604) transplanted]. Six percent of the offers (n = 1,832) (n = 771 hearts) were turned down due to distance, with 676 of the hearts never transplanted. Based on the modeling and using an ESHP time of 5.5 hours, 84% (n = 570/676) of hearts turned down due to distance could be utilized by pediatric programs. This proportion increased to 100% with 10 hours of support time. By addressing prolonged ischemic time due to distance, ESHP has the potential to increase the number of donors utilized in pediatric candidates. Although no device exists for pediatrics, this analysis lends support to the importance of developing this technology.

Family perspectives of ex situ heart perfusion.

BACKGROUND: Pediatric patients awaiting a heart transplant have high waitlist mortality. Several strategies have been utilized to decrease waiting times, but a mortality risk still exists. New medical technologies may improve waiting times and associated mortality. Ex situ heart perfusion (ESHP) is one such technology, which can decrease the impact of cold ischemia on the donor heart and allow for a longer out-of-body time. Adoption of such technology in pediatric heart transplantation will require support from end users, including patient and families. The aim of this qualitative study was to report the perspectives of families with experience related to pediatric HTx toward ESHP. METHODS: Semistructured interviews were conducted with 12 parents or guardians of children who were awaiting or received heart transplantation. Interviews were transcribed, and data were analyzed using qualitative content analysis. RESULTS: Participants expressed varied awareness and knowledge of ESHP. Independent of their understanding of ESHP, all purported that ESHP was an excellent idea and that this technology should be implemented in the pediatric population. They did not identify fundamentally different ethical issues or concerns for ESHP being used relative to other medical technologies. Overall, most participants described consent processes for ESHP should be like any other procedure. All agreed that the surgeon should continue to describe the overall health of the donor heart, provide their medical recommendations, and allow families to have the final say. CONCLUSIONS: The concepts described by the parents and guardians are important in moving this novel technology forward. This information will serve the basis for knowledge translation that will provide educational resources to broaden the understanding and reach of ESHP.

Infants less than or equal to 2.5 kg have increased mortality and worse motor neurodevelopmental outcomes at 2 years of age after Norwood-Sano palliation.

Objectives: In infants with single-ventricle congenital heart disease, prematurity and low weight at the time of the Norwood operation are risk factors for mortality. Reports assessing outcomes (including neurodevelopment) post Norwood palliation in infants ≤2.5 kg are limited. Methods: All infants who underwent a Norwood-Sano procedure between 2004 and 2019 were identified. Infants ≤2.5 kg at the time of the operation (cases) were matched 3:1 with infants >3.0 kg (comparisons) for year of surgery and cardiac diagnosis. Demographic and perioperative characteristics, survival, and functional and neurodevelopmental outcomes were compared. Results: Twenty-seven cases (mean ± standard deviation: weight 2.2 ± 0.3 kg and age 15.6 ± 14.1 days at surgery) and 81 comparisons (3.5 ± 0.4 kg and age 10.9 ± 7.9 days at surgery) were identified. Post-Norwood, cases had a longer time to lactate ≤2 mmol/L (33.1 ± 27.5 vs 17.9 ± 12.2 hours, P < .001), longer duration of ventilation (30.5 ± 24.5 vs 18.6 ± 17.5 days, P = .005), greater need for dialysis (48.1% vs 19.8%, P = .007), and greater need for extracorporeal membrane oxygenation support (29.6% vs 12.3%, P = .004). Cases had significantly greater postoperative (in-hospital) (25.9% vs 1.2%, P < .001) and 2-year (59.2% vs 11.1%, P < .001) mortality. Neurodevelopmental assessment showed the following for cases versus comparisons, respectively: cognitive delay (18.2% vs 7.9%, P = .272), language delay (18.2% vs 11.1%, P = .505), and motor delay (27.3% vs 14.3%, P = .013). Conclusions: Infants ≤2.5 kg at Norwood-Sano palliation have significantly increased postoperative morbidity and mortality up to 2-year follow-up. Neurodevelopmental motor outcomes were worse in these infants. Additional studies are warranted to assess the outcome of alternative medical and interventional treatment plans in this patient population.

Predicting outcomes following short-term ventricular assist device implant with the MELD-XI score.

BACKGROUND: Short-term continuous flow (STCF) ventricular assist devices (VADs) are utilized in adults with cardiogenic shock; however, mortality remains high. Previous studies have found that high pre-operative MELD-XI scores in durable VAD patients are associated with mortality. The use of the MELD-XI score to predict outcomes in STCF-VAD patients has not been explored. We sought to determine the relationship between MELD-XI and outcomes in adults with STCF-VADs. METHODS: This was a retrospective review of adults implanted with STCF-VADs between 2009 and 2019. Receiver operating characteristic (ROC) analysis was performed to predict outcomes and Kaplan-Meier analysis was done to assess survival. RESULTS: Seventy-nine patients were included with a median MELD-XI score of 21.2 (IQR 13.5, 27.0). Patients with an unsuccessful wean from support (p < 0.001) or major post-operative bleeding (p = 0.03) had significantly higher pre-implant MELD-XI scores. The optimal MELD-XI cut-point for mortality was 24.9 with 27.8 for major bleeding. Survival was worse among patients in the high-risk MELD-XI group, however, not statistically significant (p = 0.09). Prior ECMO support, but not MELD-XI, was an independent predictor of unsuccessful wean (p = 0.03). CONCLUSIONS: Pre-operative MELD-XI score was a moderate predictor of unsuccessful wean with limited utility in predicting bleeding in patients on STCF-VAD support. This scoring system may be useful in the clinical setting for pre-implant risk stratification and counseling among patients and outcomes.

Percutaneous Treatment of Ascending Aortic Obstruction in a Young Child After Orthotopic Heart Transplantation.

We report a case of a 14-month-old child with ascending aortic obstruction (AAO) post cardiac transplantation, who underwent successful percutaneous ascending aortic stent angioplasty. Congenital or acquired AAO is typically treated with surgical augmentation. The experience with percutaneous techniques is limited and often avoided due to challenges with equipment stability and proximity to coronary arteries and aortic valve leaflets. This case highlights that a percutaneous approach to relief of AAO is a feasible alternative even in small children utilizing a newer pre-mounted stent.

Ex situ heart perfusion for optimization of pediatric donor organ utilization: Attitudes and perceptions.

BACKGROUND: Children with heart failure have the highest mortality while awaiting transplantation. Ex situ heart perfusion (ESHP), a method for continuous perfusion of the donor heart, has the potential to improve access to transplant by increasing travel distance between donor and recipient. An adult ESHP device is currently available, but as of yet there is no pediatric device. The aim of this study was to evaluate current knowledge of ESHP among pediatric heart transplant practitioners, define potential barriers, and identify uses of this novel technology. METHODS: An electronic survey was developed to assess perspectives of international pediatric heart transplant stakeholders (n = 68) on ESHP. Select questions were analyzed to evaluate for associations between groups of respondents and patterns of response. RESULTS: Most respondents were familiar but <10% had clinically utilized ESHP. There was optimism that ESHP could decrease waitlist mortality. Respondents were concerned about potential device malfunction and lack of long-term outcomes. There were no differences found in terms of ESHP familiarity among age groups, practitioner center volume, country of work, or discipline. CONCLUSIONS: ESHP has the potential to expand the pediatric heart donor pool and decrease waitlist mortality. More education on outcomes and risks/benefits is needed in order to promote widespread adoption.

The influence of renal disease on outcomes and cardiac remodeling following surgical mitral valve replacement.

OBJECTIVES: Chronic kidney disease (CKD) is increasingly prevalent in patients undergoing mitral valve replacement (MVR). While CKD is known to result in suboptimal outcomes for patients with mitral valve disease, there is limited literature evaluating the long-term outcomes and cardiac remodeling of patients with CKD undergoing MVR. We present the first analysis coupling long-term outcomes of combined morbidity, mortality, and cardiac remodeling post-MVR in patients with CKD. METHODS: Patients with varying degrees of CKD undergoing MVR from 2004 to 2018 were compared. Patients were grouped by estimated glomerular filtration rate (eGFR) > 90 mL/min/1.73m2 (n = 109), 60-89 mL/min/1.73m2 (450), 30-59 mL/min/1.73m2 (449), < 30 mL/min/1.73m2 (60). The primary outcome was mortality. Secondary outcomes included measures of postoperative morbidity and cardiac remodeling. RESULTS: One-year mortality was significantly increased in patients with eGFR < 30 (p = 0.023). Mortality at 7 years was significantly increased in patients with eGFR < 30 mL/min/1.73m2 (p < 0.001). Multivariable regression analysis of 7-year all-cause mortality indicated an eGFR of 15 mL/min/1.73m2 (HR 4.03, 95% CI 2.54-6.40) and 30 mL/min/1.73m2 (HR 2.17 95% CI 1.55-3.05) were predictive of increased mortality. Reduced eGFR predicted the development of postoperative sepsis (p = 0.002), but not other morbidities. Positive cardiac remodeling of the left ventricle, left atrium, and valve gradients were identified postoperatively for patients with eGFR > 30 mL/min/1.73m2 while patients with eGFR < 30 mL/min/1.73m2 did not experience the same changes. CONCLUSIONS: CKD is predictive of inferior clinical and echocardiographic outcomes in patients undergoing MVR and consequently requires careful preoperative consideration and planning. Further investigation into optimizing the postoperative outcomes of this patient population is necessary.

Quantifying the immune response to a tissue-engineered porcine extracellular matrix.

Aim: Structural valvular deterioration of xenogenic heart valve replacements is thought to be due to a chronic immune response. We sought to engineer porcine extracellular matrix that elicits minimal inflammatory immune response. Materials & methods: Whole blood, bone marrow and pericardium were collected from patients undergoing elective cardiac surgery. Porcine extracellular matrix was decellularized, reseeded with homologous mesenchymal stem cells and exposed to whole blood. Results: DAPI stain confirmed the absence of cells after decellularization, and presence of mesenchymal stem cells after recellularization. There was a significant reduction in IL-1ß and TNF-α production in the recellularized matrix. Conclusion: Recellularization of porcine matrix is successful at attenuating the xenogenic immune response and may provide a suitable scaffold to address the current limitations of prosthetic heart valve replacements.

Deterioration of tissue heart valve replacements is thought to be due to a chronic immune response. We sought to remove cells from a pig derived tissue and replace those cells with human stem cells to create a scaffold that results in a reduced immune response. Whole blood, bone marrow and pericardium were collected from patients undergoing elective cardiac surgery. The pig derived tissue had the cells removed, were replaced with human stem cells and exposed to whole blood. Tissue stain confirmed the absence of cells after removal, and presence of stem cells after replacement of cells. There was a significant reduction in markers of immune response in the recellularized tissue. Removal of cells from pig derived tissue and replacement with human stem cells is successful at reducing the immune response to animal tissue and may provide a suitable scaffold to address the current limitations of heart valve replacement options.

Oxidative stress and related metabolic alterations are induced in ex situ perfusion of donated hearts regardless of the ventricular load or leukocyte depletion.

We sought to determine the role of donor blood circulating leukocytes in mediating oxidative stress and inflammation during normothermic ex situ heart perfusion (ESHP). Normothermic ESHP allows preservation of donated heart in a perfused, dynamic state, preventing ischemia. However, the cardiac function declines during ESHP, limiting the potential of this method for improvement of the outcomes of transplantation and expanding the donor pool. Extracorporeal circulation-related oxidative stress plays a critical role in the functional decline of the donor heart. Hearts from domestic pigs were perfused in working mode (WM, whole blood-based or leukocyte-depleted blood-based perfusate) or nonworking mode. Markers of oxidative stress and responsive glucose anabolic pathways were induced in the myocardium regardless of left ventricular load. Myocardial function during ESHP as well as cardioprotective mechanisms were preserved better in WM. Leukocyte-depleted perfusate did not attenuate tissue oxidative stress or perfusate proinflammatory cytokines and did not improve functional preservation. Although ESHP is associated with ongoing oxidative stress and metabolic alteration in the myocardium, preserved cardioprotective mechanisms in WM may exert beneficial effects. Leukocyte depletion of the perfusate may not attenuate inflammation and oxidative stress effectively or improve the functional preservation of the heart during ESHP.

The Impact of Ex Situ Heart Perfusion in Pediatric Transplantation: An Analysis of the United Network for Organ Sharing Registry.

Ex situ heart perfusion (ESHP) has increased the pool of donors in adults. However, this is not true in pediatrics due to lack of devices. Therefore, we sought to understand organ refusal in pediatrics and estimate donor heart usage with ESHP. Donor hearts offered to pediatrics were identified from the United Network for Organ Sharing (UNOS) Database (2000-2019). A linear regression model was built to predict average travel speed, and the extended maximum permitted distance with ESHP was calculated. This extended distance was compared with the policy for maximum travel distance. There were 33,708 donor offers (n = 10,807 hearts) to pediatric programs (24.1% [n = 2,604] transplanted). Six percent of the offers (n = 1,832) (n = 771 hearts) were turned down due to distance, with 676 of the hearts never transplanted. Based on the modeling and using an ESHP time of 5.5 hours, 84% (n = 570/676) of hearts turned down as distance could be utilized by pediatric programs. This proportion increased to 100% with 10 hours of support time. By addressing prolonged ischemic time due to distance, ESHP has the potential to increase the number of donors utilized in pediatric candidates. While no device exists for pediatrics, this analysis lends support to the importance of developing this technology.

Barriers and misconceptions of ex situ heart perfusion in pediatric donation.

BACKGROUND: Despite efforts, pediatric HTx candidates continue to have high waitlist mortality due to limited donor availability. However, there is a significant number of offered hearts not used due to concerns of viability. ESHP is a method for continuous perfusion of the donor heart that allows assessment and extended out-of-body time. It is imperative to understand healthcare stakeholders' perspectives on ESHP for implementation. Therefore, the aims of this qualitative study were to: (1) Explore pediatric stakeholders' perspectives toward ESHP; and (2) Identify barriers to widespread adoption of this technology. METHODS: Virtual focus groups were completed with pediatric HTx healthcare professional stakeholders. Following transcription of audio-recordings, the material was analyzed using content analysis. RESULTS: Four focus groups were completed with 17 participants, representing 12 institutions and three countries. Focus groups revealed varied understanding of both current and potential uses of ESHP. Participants did see the potential benefits of extending out-of-body time for and the ability to evaluate donor heart quality. However, concerns were expressed relating to patient selection, wait-list times, post-HTx outcomes, adverse events, and technical issues. These were felt to be important to understand in order to justify the costs of ESHP and impact on the healthcare system. CONCLUSIONS: This project represents the first qualitative formative evaluation of ESHP in pediatrics. The knowledge gained from stakeholders will form the basis for education initiatives, clinical trial design, and roll-out of new ESHP technologies designed for pediatrics.

Model of Acute Liver Failure in an Isolated Perfused Porcine Liver-Challenges and Lessons Learned.

Acute liver failure (ALF) is a rare but devastating disease associated with substantial morbidity and a mortality rate of almost 45%. Medical treatments, apart from supportive care, are limited and liver transplantation may be the only rescue option. Large animal models, which most closely represent human disease, can be logistically and technically cumbersome, expensive and pose ethical challenges. The development of isolated organ perfusion technologies, originally intended for preservation before transplantation, offers a new platform for experimental models of liver disease, such as ALF. In this study, female domestic swine underwent hepatectomy, followed by perfusion of the isolated liver on a normothermic machine perfusion device. Five control livers were perfused for 24 h at 37 °C, while receiving supplemental oxygen and nutrition. Six livers received toxic doses of acetaminophen given over 12 h, titrated to methemoglobin levels. Perfusate was sampled every 4 h for measurement of biochemical markers of injury (e.g., aspartate aminotransferase [AST], alanine aminotransferase [ALT]). Liver biopsies were taken at the beginning, middle, and end of perfusion for histological assessment. Acetaminophen-treated livers received a median dose of 8.93 g (8.21-9.75 g) of acetaminophen, achieving a peak acetaminophen level of 3780 µmol/L (3189-3913 µmol/L). Peak values of ALT (76 vs. 105 U/L; p = 0.429) and AST (3576 vs. 4712 U/L; p = 0.429) were not significantly different between groups. However, by the end of perfusion, histology scores were significantly worse in the acetaminophen treated group (p = 0.016). All acetaminophen treated livers developed significant methemoglobinemia, with a peak methemoglobin level of 19.3%, compared to 2.0% for control livers (p = 0.004). The development of a model of ALF in the ex vivo setting was confounded by the development of toxic methemoglobinemia. Further attempts using alternative agents or dosing strategies may be warranted to explore this setting as a model of liver disease.

Preclinical systematic review & meta-analysis of cyclosporine for the treatment of myocardial ischemia-reperfusion injury.

Background: Though best known for its immunosuppressant effects, cyclosporine A (CsA) has also been studied as a treatment to mitigate ischemia-reperfusion injury (IRI) by its inhibition of the mitochondria permeability transition pore (mPTP). Despite numerous preclinical studies supporting its benefit in reducing infarct size following myocardial IRI, large randomized controlled clinical trials have been unable to show a beneficial effect. Exploring existing preclinical data can give us the opportunity to revisit some the assumptions that may have led to the failure of these studies to translate clinically. Herein, we present a systematic review of preclinical studies testing CsA to attenuate myocardial IRI (PROSPERO CRD42020159620). Methods: We conducted a systematic search of health research databases Ovid MEDLINE, Ovid EMBASE, Web of Science BIOSIS, and Scopus, as well as Cochrane and PROSPERO systematic review databases, on March 9, 2022 for non-human in vivo animal studies of myocardial IRI, using CsA as a treatment that reported clinically relevant outcomes. Bias was assessed using the Systematic Review Centre for Laboratory Animal Experimentation's risk of bias tool and a modified Collaborative Approach to Meta Analysis and Review of Animal Data from Experimental Studies checklist. Sub-group meta-analyses were conducted to identify potential factors influencing outcomes. Results: We identified 71 studies, 59 of which were studies of coronary occlusion. Overall, 75% of studies reported a clear positive effect of CsA in mitigating myocardial IRI by some clinically relevant parameter (e.g., infarct size). A meta-analysis including 43 coronary occlusion studies showed an overall reduction in infarct size with CsA treatment (16.09%; 95% CI: -18.50% to -13.67%). Subgroup meta-analyses identified species, age, timing of administration, and duration of ischemia as factors potentially affecting the efficacy of CsA in the setting of myocardial IRI. Conclusions: Our systematic review and meta-analysis identifies questions that have yet to be answered by preclinical studies, highlighting important differences between these and clinical studies that should be addressed prior to proceeding with any further clinical studies using CsA to treat IRI in the heart or other organs. We also use the example of CsA to highlight general considerations for researchers attempting to translate animal studies into the clinical setting.

The evaluation of constant coronary artery flow versus constant coronary perfusion pressure during normothermic ex situ heart perfusion.

BACKGROUND: Evidence suggests that hearts that are perfused under ex-situ conditions lose normal coronary vasomotor tone and experience contractile failure over a few hours. We aimed to evaluate the effect of different coronary perfusion strategies during ex situ heart perfusion on cardiac function and coronary vascular tone. METHODS: Porcine hearts (n = 6 each group) were perfused in working mode for 6 hours with either constant aortic diastolic pressure (40 mmHg) or constant coronary flow rate (500 mL/min). Functional and metabolic parameters, cytokine profiles, cardiac and vascular injury, coronary artery function and oxidative stress were compared between groups. RESULTS: Constant coronary flow perfusion demonstrated better functional preservation and less edema formation (Cardiac index: flow control = 8.33 vs pressure control = 6.46 mL·min-1·g-1, p = 0.016; edema formation: 7.92% vs 19.80%, p < 0.0001). Pro-inflammatory cytokines, platelet activation as well as endothelial activation were lower in the flow control group. Similarly, less cardiac and endothelial injury was observed in the constant coronary flow group. Evaluation of coronary artery function showed there was loss of coronary autoregulation in both groups. Oxidative stress was induced in the coronary arteries and was relatively lower in the flow control group. CONCLUSIONS: A strategy of controlled coronary flow during ex situ heart perfusion provides superior functional preservation and less edema formation, together with less myocardial damage, leukocyte, platelet, endothelial activation, and oxidative stress. There was loss of coronary autoregulation and decrease of coronary vascular resistance during ESHP irrespective of coronary flow control strategy. Inflammation and oxidative stress state in the coronary vasculature may play a role.

Recellularized bovine pericardium with autologous mesenchymal stem cells reduces immune activation.

INTRODUCTION: Current bioprosthetic heart valve replacement options are limited by structural valvular deterioration (SVD) due to an immune response to the xenogenic scaffold. Autologous mesenchymal stem cell (MSC) recellularization is a method of concealing xenogenic scaffolds, preventing recipient immune recognition of xenogenic tissue heart valves, and potentially leading to reduction in SVD incidence. The purpose of this study is to examine the effects of autologous MSC recellularized tissue on the immune response of human whole blood to bovine pericardium (BP). We hypothesized that autologous MSC recellularization of BP will result in reduced pro-inflammatory cytokine production equivalent to autologous human pericardium. METHODS: Bone marrow, human pericardium, and whole blood were collected from adult patients undergoing elective cardiac surgery. Decellularized BP underwent recellularization with autologous MSCs, followed by co-incubation with autologous whole blood. Immunohistochemical, microscopic, and quantitative immune analysis approaches were used. RESULTS: We demonstrated that native BP, exposed to human whole blood, results in significant TNF-α and IL1ß production. When decellularized BP is recellularized with autologous MSCs and exposed to whole blood, there is a significant reduction in TNF-α and IL1ß production. Importantly, recellularized BP exposed to whole blood had similar production of TNF-α and IL1ß when compared to autologous human pericardium exposed to human whole blood. CONCLUSION: Our results suggest that preventing initial immune activation with autologous MSC recellularization may be an effective approach to decrease the recipient immune response, preventing recipient immune recognition of xenogeneic tissue engineered heart valves, and potentially leading to reduction in SVD incidence.

Ventricular assist device support following pediatric heart transplantation.

BACKGROUND: VAD support for early graft failure after HTx is a rare event in pediatrics. METHODS: We retrospectively describe our single-center experience with post-HTx VAD support in a cohort of patients transplanted between 01/05 and 12/20. RESULTS: Nine patients underwent VAD insertion in the early post-HTx period [median age 6.1 years (Range 0.3-20.3), median weight 17.6 kg (Range 3.5-65.0), and congenital heart disease (67%)]. Of the nine patients with early graft failure, almost half (44%) were implanted after 2015 and all of these patients had a pre-HTx plan for possible post-transplant VAD insertion. Time to VAD implant was a median of 0 day (Range 0-11). Total time on VAD support was a median of 12 days (Range 3.0-478.0). Two-thirds (n = 6; 67%) of the patients were weaned from support, retransplanted (11%) and two patients died (22%). In all of the patients where post-HTx VAD was anticipated there was 100% survival. CONCLUSIONS: In this small patient series, post-HTx VAD was a useful measure in selected patients especially with pre-HTx planning. However, more shared experiences to verify these findings are needed.