Hemodynamics in pig-to-baboon heterotopic thoracic cardiac xenotransplantation: Recovery from perioperative cardiac xenograft dysfunction and impairment by cardiac overgrowth.

INTRODUCTION: Orthotopic cardiac xenotransplantation has seen notable improvement, leading to the first compassionate use in 2022. However, it remains challenging to define the clinical application of cardiac xenotransplantation, including the back-up strategy in case of xenograft failure. In this regard, the heterotopic thoracic technique could be an alternative to the orthotopic procedure. We present hemodynamic data of heterotopic thoracic pig-to-baboon transplantation experiments, focusing on perioperative xenograft dysfunction and xenograft overgrowth. METHODS: We used 17 genetically modified piglets as donors for heterotopic thoracic xenogeneic cardiac transplantation into captive-bred baboons. In all animals, pressure probes were implanted in the graft's left ventricle and the recipient's ascending aorta and hemodynamic data (graft pressure, aortic pressure and recipient's heart rate) were recorded continuously. RESULTS: Aortic pressures and heart rates of the recipients' hearts were postoperatively stable in all experiments. After reperfusion, three grafts presented with low left ventricular pressure indicating perioperative cardiac dysfunction (PCXD). These animals recovered from PCXD within 48 h under support of the recipient's heart and there was no difference in survival compared to the other 14 ones. After 48 h, graft pressure increased up to 200 mmHg in all 17 animals with two different time-patterns. This led to a progressive gradient between graft and aortic pressure. With increasing gradient, the grafts stopped contributing to cardiac output. Grafts showed a marked weight increase from implantation to explantation. CONCLUSION: The heterotopic thoracic cardiac xenotransplantation technique is a possible method to overcome PCXD in early clinical trials and an experimental tool to get a better understanding of PCXD. The peculiar hemodynamic situation of increasing graft pressure but missing graft's output indicates outflow tract obstruction due to cardiac overgrowth. The heterotopic thoracic technique should be successful when using current strategies of immunosuppression, organ preservation and donor pigs with smaller body and organ size.

Early postoperative hemodynamic instability after heart transplantation - incidence and metabolic indicators.

BACKGROUND: Primary graft dysfunction (PGD) is the main cause of death in the first 30 days after heart transplantation (HTX), accounting for approximately 40% of mortality. The study's primary aim was to assess the incidence of PGD, following the International Society for Heart and Lung Transplantation consensus, and to compare it with the incidence of significant postoperative hypotension despite administration of high-dose inotropes and vasoconstrictors. The secondary aim of the study was to determine changes in biochemical markers that accompany the phenomenon. METHODS: Forty-five patients who underwent HTX between 2010 and 2015 were enrolled in this study, and detailed hemodynamic and metabolic data from the first 48 postoperative hours were collected and analyzed. Hemodynamic instability was defined as significant postoperative hypotension (mean arterial pressure (MAP) < 60 mmHg) combined with a high inotrope score (> 10). Data for long-term mortality were obtained from the population registration office. RESULTS: PGD incidence was relatively low (17.8%); however, hemodynamic instability was common (40%). Among unstable patients, MAP was insufficient for end-organ perfusion (51.4 ± 9.5 mmHg) but no decrease in left ventricular function was observed (cardiac index, 2.65 ± 0.6 l/min/m2; left ventricular ejection fraction, 52.9 ± 15.5%). Within this group, mean systemic vascular resistance index (961 ± 288 dyn*s*m2/cm5) was low despite receiving high doses of vasoactive agent (norepinephrine 0.21 (0.06-0.27) µg/kg/min during first 24 h postoperatively and 0.21 (0.01-0.27) µg/kg/min during next 24 h postoperatively). After HTX, serum lactate levels were initially significantly higher in patients with hemodynamic instability (p = 0.002); however, impaired lactate clearance was not observed (p = 0.366), and lactate levels normalized within the first 24 h postoperatively. Postoperative hemodynamic instability altered the long-term outcome and increased 5-year mortality after HTX (p = 0.034). CONCLUSIONS: Hemodynamic instability is a more common phenomenon than PGD. Only early postoperative serum lactate levels correspond with hemodynamic instability following HTX. Postoperative hemodynamic instability is associated with poor long-term survival among HTX recipients.

Donor Left Ventricular Function Assessed by Echocardiographic Strain is a Novel Predictor of Primary Graft Failure After Orthotopic Heart Transplantation.

OBJECTIVES: This study sought to determine the utility of donor left ventricular function assessment by echocardiographic left ventricular global longitudinal strain (LV GLS) in predicting primary graft failure (PGF) after orthotopic heart transplantation (HT). DESIGN: Retrospective, observational study. SETTING: Tertiary referral hospital. PARTICIPANTS: Adult patients (>18 years) who underwent isolated HT. INTERVENTIONS: Demographic, clinical, and echocardiographic data were collected on 100 patients who underwent HT between January 2010 and December 2019 at the authors' institution. The respective donor variables, as well as procedural factors, were reviewed and analyzed to assess their independent association with PGF. Standard donor echocardiographic measurements were supplemented by two-dimensional speckle-tracking echocardiography to obtain LV GLS. PGF was defined as per the International Society for Heart and Lung Transplantation 2014 consensus statement. MEASUREMENTS AND MAIN RESULTS: PGF occurred in 40 of the 100 patients (40%). Initial univariate analysis found that RADIAL score, donor ejection fraction, and donor LV GLS were associated with PGF. However, in a multivariate Cox regression analysis, only RADIAL score and donor LV GLS remained significant predictors of PGF, with a p < 0.001. By receiver operating characteristic curve analysis, LV GLS at a cut-off value of -11.5% showed the greatest area under the curve (area under the curve = 0.889; 95% confidence interval, 0.826-0.952) and predicted PGF with 92.5% sensitivity and 65% specificity. CONCLUSIONS: Impaired donor LV GLS was proven to be an independent predictor of PGF after HT.

Incidence, Management, and Prognosis of Graft Failure and Autologous Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND: This study presents outcomes of management in graft failure (GF) after allogeneic hematopoietic stem cell transplantation (HCT) and provides prognostic information including rare cases of autologous reconstitution (AR). METHODS: We analyzed risk factors and outcomes of primary and secondary GF, and occurrence of AR in 1,630 HCT recipients transplanted over period of 18 years (January 2000-September 2017) at our center. RESULTS: Primary and secondary GF occurred in 13 (0.80%), and 69 patients (10-year cumulative incidence, 4.5%) respectively. No peri-transplant variables predicted primary GF, whereas reduced intensity conditioning (RIC) regimen (relative risk [RR], 0.97-28.0, P < 0.001) and lower CD34⁺ cell dose (RR, 2.44-2.84, P = 0.002) were associated with higher risk of secondary GF in multivariate analysis. Primary GF demonstrated 100% mortality, in the secondary GF group, the 5-year Kaplan-Meier survival rate was 28.8%, relapse ensued in 18.8%, and AR was observed in 11.6% (n = 8). In survival analysis, diagnosis of aplastic anemia (AA), chronic myeloid leukemia and use of RIC had a positive impact. There were 8 patients who experienced AR, which was rarely reported after transplantation for acute leukemia. Patient shared common characteristics such as young age (median 25 years), use of RIC regimen, absence of profound neutropenia, and had advantageous survival rate of 100% during follow period without relapse. CONCLUSION: Primary GF exhibited high mortality rate. Secondary GF had 4.5% 10-year cumulative incidence, median onset of 3 months after HCT, and showed 5-year Kaplan-Meier survival of 28.8%. Diagnosis of severe AA and use of RIC was both associated with higher incidence and better survival rate in secondary GF group. AR occurred in 11.6% in secondary GF, exhibited excellent prognosis.

In-hospital postoperative infection after heart transplantation: Risk factors and development of a novel predictive score.

INTRODUCTION: Infection is one of the most significant complications following heart transplantation (HT). The aim of this study was to identify specific risk factors for early postoperative infections in HT recipients, and to develop a multivariable predictive model to identify HT recipients at high risk. METHODS: A single-center, observational, and retrospective study was conducted. The dependent variable was in-hospital postoperative infection. We examined demographic and epidemiological data from donors and recipients, surgical features, and adverse postoperative events as independent variables. Backwards, stepwise multivariable logistic regression with a P-value < 0.05 was used to identify clinical factors independently associated with the risk of in-hospital postoperative infections following HT. RESULTS: Six hundred seventy-seven patients were included in this study. During the in-hospital postoperative period, 348 episodes of infection were diagnosed in 239 (35.9%) patients. Seven variables were identified as independent clinical predictors of early postoperative infection after HT: history of diabetes mellitus, previous sternotomy, preoperative mechanical ventilation, primary graft failure, major surgical bleeding, use of mycophenolate mofetil, and use of itraconazole. Based on the results of multivariable models, we constructed a 7-variable (8-point) score to predict the risk of in-hospital postoperative infection in HT recipients, which showed a reasonable ability to predict the risk of in-hospital postoperative infection in this population. Prospective external validation of this new score is warranted to confirm its clinical applicability. CONCLUSIONS: In-hospital postoperative infection is a common complication after HT, affecting 35% of patients who underwent this procedure at our institution. Diabetes mellitus, previous sternotomy, preoperative mechanical ventilation, primary graft failure, major surgical bleeding, use of mycophenolate mofetil, and itraconazole were all independent clinical predictors of early postoperative infection after HT.

Real Time Immunophenotyping of Leukocyte Subsets Early after Double Cord Blood Transplantation Predicts Graft Function.

Cord blood transplantation (CBT) recipients are at increased risk for delayed engraftment and primary graft failure, complications that are often indistinguishable early post-transplantation. Current assays fail to accurately identify recipients with slow hematopoietic recovery and distinguish them from those with pending graft failure. To address this, we prospectively examined the kinetics of immune cell subset recovery in the peripheral blood of 39 patients on days +7 and +14 after double-unit CBT (dCBT) by multiparametric flow cytometry analysis, which we term real-time immunophenotyping (RTIP). RTIP analysis at day +14 revealed distinctive patterns of reconstitution and, importantly, identified patients with slow hematopoietic recovery who went on to engraft. Strikingly, higher absolute numbers of circulating monocytes and natural killer cells at day +14 were predictive of engraftment, but only the absolute number of circulating monocytes was significantly correlated with time to engraftment. This is the first evidence that RTIP on patient peripheral blood mononuclear cells early after dCBT is technically feasible and can be used as a "signature" for predicting the kinetics of hematopoietic recovery. Furthermore, RTIP is a time- and cost-efficient methodology that has the potential to become a clinically feasible diagnostic tool to guide therapeutic interventions in high-risk patients; therefore, its utility should be evaluated in a large cohort of patients.

Effect of early allograft dysfunction on outcomes following liver transplantation.

Early allograft dysfunction (EAD) following liver transplantation (LT) remains a challenge for patients and clinicians. We retrospectively analyzed the effect of pre-defined EAD on outcomes in a 10-year cohort of deceased-donor LT recipients with clearly defined exclusion criteria. EAD was defined by at least one of the following: AST or ALT >2000 IU/L within first-week post-LT, total bilirubin ≥10 mg/dL, and/or INR ≥1.6 on post-operative day 7. Ten patients developed primary graft failure and were analyzed separately. EAD occurred in 86 (36%) recipients in a final cohort of 239 patients. In univariate and multivariate analyses, EAD was significantly associated with mechanical ventilation ≥2 days or death on days 0, 1, PACU/SICU stay >2 days or death on days 0-2 and renal failure (RF) at time of hospital discharge (all P<.05). EAD was also significantly associated with higher one-year graft loss in both uni- and multivariate Cox hazard analyses (P=.0203 and .0248, respectively). There was no difference in patient mortality between groups in either of the Cox proportional hazard models. In conclusion, we observed significant effects of EAD on short-term post-LT outcomes and lower graft survival.

A multicenter study of primary graft failure after infant heart transplantation: impact of extracorporeal membrane oxygenation on outcomes.

Primary graft failure is the major cause of mortality in infant HTx. The aim of this study was to characterize the indication and outcomes of infants requiring ECMO support due to primary graft failure after HTx. We performed a retrospective review of all infants (<1 yr) who underwent Htx from three institutions. From 1999 to 2008, 92 infants (<1 yr) received Htx. Sixteen children (17%) required ECMO after Htx due to low cardiac output syndrome. Eleven (69%) infants were successfully weaned off ECMO, and 9 (56%) infants were discharged with a mean follow-up of 2.3 ± 2.5 yr. Mean duration of ECMO in survivors was 5.4 days (2-7 days) compared with eight days (2-10 days) in non-survivors (p = NS). The five-yr survival rate for all patients was 75%; however, the five-yr survival rate was 40% in the ECMO cohort vs. 80% in the non-ECMO cohort (p = 0.0001). Graft function within one month post-Htx was similar and normal between ECMO and non-ECMO groups (shortening fraction = 42 ± 3 vs. 40 ± 2, p = NS). For infants, ECMO support for primary graft failure had a lower short-term and long-term survival rate vs. non-ECMO patients. Duration of ECMO did not adversely impact graft function and is an acceptable therapy for infants after HTx for low cardiac output syndrome.

Usefulness of biomarkers to predict prognosis after heart transplant.

INTRODUCTION AND OBJECTIVES: Heart transplant (HT) represents a major physiological stress, resulting in elevated levels of analytical biomarkers. This study aimed to determine whether changes in biomarker levels after HT can identify patients with a poor prognosis. METHODS: A prospective longitudinal noninterventional study was conducted in 149 consecutive patients undergoing HT from July 2017 to July 2023. Biomarkers were assessed before HT and at 6, 24, 48, 72, and 96hours after HT. The biomarkers analyzed were high-sensitivity troponin T, N-terminal pro-B-type natriuretic peptide (NT-proBNP), creatinine, and lactic acid. The primary outcome was a composite of death and severe primary graft failure (PGF). RESULTS: NT-proBNP and troponin levels remained highly elevated throughout the period and stabilized from the first 24hours post-HT. Lactate levels stabilized after the first 24hours, and creatinine from the second day onward. Exitus occurred in 23 (15%) of the patients, and severe PGF in 26 (17%). All biomarkers were significantly associated with the incidence of the combined event (P <.0001). Receiver operating characteristic curve analysis at 24hours showed significant areas under the curve (P=.0001). The greatest discriminatory power was observed for the NT-proBNP curve. A value of 10 000 pg/mL had a sensitivity of 90% and specificity of 80%. CONCLUSIONS: A significant elevation of post-HT analytical biomarkers was associated with mortality and/or severe PGF. Among the biomarkers analyzed, NT-proBNP was the most accurate in classifying patients.

Lesson learned in pediatric haploidentical transplantation in a low-resource environment: delivering melphalan IV and using low dose radiation reduce graft failure.

Objectives: Primary graft failure (pGF) after hematopoietic stem-cell transplant is associated with considerable morbidity and mortality. The incidence in haplo-HSCT has been reported to be between 0% and 30%. In 2018, we identified a pGF incidence of 35% in our pediatric haplo-HSCT recipients with hematologic malignancies, which motivated us to enact changes to the conditioning regimen.Methods: We performed a single-center prospective, pre-post study of consecutive patients under 16 years with hematologic malignancies, from January 2015 to December 2022 who received a haplo-HSCT. Twenty-six pediatric patients received a haplo-HSCT before September 2018 (G1) and 36 patients after (G2). The main conditioning regimen for G1 was myeloablative with Flu/Cy/Bu, and for G2 the main regimen was reduced intensity Flu/Cy/Mel/TBI2.Results: Nine patients (35%) in G1 had primary graft failure, while in G2 there were no patients with pGF. The median follow-up for G1 was 15.9 months, and for G2 was 24.8 months, with an estimated overall survival at 12 months of 63% (95% CI 47-76) versus 85% (95% CI 73-93), and at 24 months of 47% (95% CI 31-64) versus 70% (95% CI 54-82) respectively (p = .007).Conclusion: After September 2018 conditioning regimen modifications were implemented with the objective of reducing primary failure, consisting mainly of switching from busulfan to melphalan as the alkylating agent of choice, and adding, when clinically possible TBI. Primary failure has been significantly reduced in our institution since then.

Impact of prolonged ischemic time on pediatric heart transplantation outcomes: Improved outcomes in the most recent era.

BACKGROUND: Impacts of ischemic time (IT) on pediatric heart transplant outcomes are multifactorial. We aimed to analyze the effect of prolonged IT on graft loss after pediatric heart transplantation. We hypothesized that graft survival with prolonged IT has improved across eras. METHODS: Patients <18 years old in the Pediatric Heart Transplant Society database were included (N=6,765) and stratified by diagnosis and era (1993-2004, 2005-2009, and 2010-2019). Severe graft failure (SGF) was defined as death, retransplant, or need for mechanical circulatory support in the first 7 days post-transplant. Descriptive statistical methods were used to compare differences between patient characteristics and IT. Kaplan-Meier survival analysis compared freedom from graft loss, rejection, and infection. Multivariable analysis was performed for graft loss and SGF (hazard and logistic regression modeling, respectively). RESULTS: Diagnoses were cardiomyopathy (N = 3,246) and congenital heart disease (CHD; N = 3,305). CHD were younger, more likely to have an IT ≥4.5 hours, and more likely to require extracorporeal membrane oxygenation or mechanical ventilation at transplant (all p < 0.001). Median IT was 3.6 hours (interquartile range 2.98-4.31; range 0-10.5). IT was associated with early graft loss (HR 1.012, 95% CI 1.005-1.019), but not when analyzed only in the most recent era. IT was associated with SGF (OR 1.016 95%CI 1.003-1.030). CONCLUSIONS: Donor IT was independently associated with an increased risk of graft loss, albeit with a small effect relative to other risk factors. Graft survival with prolonged IT has improved in the most recent era but the risk of SGF persists.

The impact of donor-specific antibodies' presence on the outcome post-allogeneic hematopoietic stem cell transplantation: a survey from a single center.

Introduction: Donor-specific antibodies (DSAs) correspond to anti-HLA antibodies of the recipient that are specifically directed to a mismatched antigen of the donor. In the setting of solid organ transplantation DSAs are associated with rejection. Their role is still debated in allogeneic cell transplantation. International guidelines recommend testing patients for DSA before transplant, and if possible, choosing a donor with negative screening. Methods: We collected clinical data of 236 recipients of alloSCT, performed at our institution from March 2019 to October 2023, to evaluate their impact on engraftment. Serum from all patients was tested for DSA. Results: 186 patients (79%) achieved sustained myeloid engraftment within day 30 post alloSCT. Thirty-two out 236 (13%) patients engrafted after day 30 post alloSCT. The median times to neutrophil engraftment and platelet engraftment were respectively 21 days (range 11-121 days) and 19 days (range 10-203 days). Fourteen out 236 patients (6%) experienced PrGF. .Twenty-nine patients (12 %) were DSA-positive. Among 29 patients with DSA positivity, 17 had a haploidentical donor and 12 had a UD donor. DSA positivity directly correlates respectively with neutrophil and platelets engraftment failure at 30 days after alloSCT (p=0.01 and p= 0.0004). Univariate Cox analysis showed that factors, including DSAs positivity, disease type, disease status, donor type, conditioning regimen, patient's age, and CD34+ were correlated with neutrophil and platelet engraftment failure at 30 days after alloSCT. Younger patients with DSA negativity, with acute leukemia, in complete response at the time of transplant, who received a higher dose of CD34+ cells from a sibling donor after a myeloablative conditioning regimen, have a reduced risk of neutrophil and platelet engraftment failure at day +30 post alloSCT.Multivariate analysis confirmed the impact of the presence of DSA only for platelet engraftment, confirming the role of type and status disease, donor type, recipient age, and CD34+ cells infused on engraftment. DSA presence has no impact on TRM, DFS, and OS. Discussion: PrGF has a multifactorial pathogenesis, where DSA is not the only player, but its impact could vary depending on the transplant platform. Thus patient screening may be helpful to choose the best donor and transplant strategy.

Effects of atrial natriuretic peptide after prolonged hypothermic storage of the isolated rat heart.

Primary graft failure (PGF) caused by ischemia-reperfusion injury (IRI) is the strongest determinant of perioperative mortality after heart transplantation. Atrial natriuretic peptide (ANP) has been found to reduce the IRI of cardiomyocytes and may be beneficial in alleviating PGF after heart transplantation, although there is a lack of evidence to support this issue. The purpose of this study was to investigate the cardioprotective effects of ANP after prolonged hypothermic storage. For this purpose, an isolated working-heart rat model was used. After the preparation, the hearts were arrested with and stored in an extracellular-based cardioplegic solution at 3-4°C for 6 h and followed by 25 min of reperfusion. The hearts were divided into four groups (n = 7 in each group) according to the timing of ANP administration: Group 1 (in perfusate before storage), Group 2 (in cardioplegia), Group 3 (in reperfusate), and control (no administration of ANP). Left ventricular functional recovery and the incidence of ventricular fibrillation (VF) were compared. ANP administration at the time of reperfusion improved the percent recovery of left ventricular developed pressure (control, 45.5 ± 10.2; Group 1, 47.4 ± 8.8; Group 2, 45.3 ± 12 vs. Group 3, 76.3 ± 7; P < 0.05) and maximum first derivative of the left ventricular pressure (control, 47.9 ± 8.7; Group 1, 46.7 ± 8.8; Group 2, 49.6 ± 10.8 vs. Group 3, 76.6 ± 7.5; P < 0.05). The incidence of VF after reperfusion did not differ significantly among these four groups (71.4, 85.7, 57.1, and 85.7% in Groups 1, 2, 3, and control, respectively). This result suggests that the administration of ANP at the time of reperfusion may have the potential to decrease the incidence of PGF after heart transplantation.

A machine learning model for prediction of 30-day primary graft failure after heart transplantation.

Background: Primary graft failure (PGF) remains the most common cause of short-term mortality after heart transplantation. The main objective was to develop and validate a risk model for prediction of short-term mortality due to PGF after heart transplantation using the ISHLT Heart Transplant Registry. Methods: We developed a non-linear artificial neural networks (ANN) model to evaluate the association between recipient-donor variables and post-transplant PGF. Patients in the ISHLT registry were randomly divided into derivation and an independent internal validation cohort. The primary endpoint was PGF defined as death within 30 days due to Graft failure or Cardiovascular causes or retransplant within 30 days for causes other than rejection. Results: Among 64,964 adult recipients transplanted between 1994 and 2013, mean age was 51 years and 22% were female. The incidence of PGF up to 30 days was 3.7%. The ANN model selected 33 of 77 risk variables as relevant for PGF prediction. The C-index in the test cohort was 0.70 (95% CI: 0.68-0.71). The risk variables which most influenced the PGF were underlying HF diagnosis, ischemia time and sex, while renal function had a lower influence. Conclusion: An ANN model to predict primary graft dysfunction was derived and independently validated. The good discrimination of the ANN model likely results from its flexibility to model potentially non-linear relationships and interactions. Whether this model with improved discrimination can assist in clinical decisions at the time of transplant should be tested.

Risk Factors for Descemet Membrane Endothelial Keratoplasty Rejection: Current Perspectives- Systematic Review.

Descemet membrane endothelial keratoplasty (DMEK) is a corneal endothelial transplantation procedure with selective removal of a patient's defective Descemet membrane and endothelium. It is replaced with a healthy donor Descemet membrane and endothelium without a stromal component. Corneal graft rejection can be at the level of epithelium, stroma as well endothelium. DMEK graft rejection is relatively less common than rejection with DSAEK or penetrating keratoplasty, and a good outcome may be achieved with prompt management. The clinical picture of DMEK rejection is usually similar to endothelial rejection in Descemet Stripping Endothelial Keratoplasty (DSEK/DSAEK), which generally manifests as pain, redness, reduction in visual acuity, stromal edema, endothelial rejection line, keratic precipitates at the back of the cornea and corneal neovascularization. However, more subtle forms of rejection or immune reactions are more common in DMEK compared to DSAEK eyes. Early clinical diagnosis, prompt intervention, and meticulous management safeguard visual acuity and graft survival in these cases. Intensive topical steroids form the mainstay in the management of DMEK rejection. Sometimes, oral or intravenous steroids or other systemic immunomodulators may be required. DMEK graft failure can be primary or secondary, and failure usually requires a second procedure in the form of repeat DMEK or DSEK or penetrating keratoplasty (PKP). A detailed literature search was performed using search engines such as Google Scholar, PubMed, and Google books, and a comprehensive review on DMEK rejection was found to be lacking. This review is a comprehensive update on the risk factors, pathophysiology, primary and secondary graft failure, recent advances in diagnosis, prevention of rejection, and updates in the management of DMEK rejection. The review also discusses the differential diagnosis of DMEK failure and rejection, prognosis, and future perspectives considering DMEK failure and rejection.

Heart graft preservation technics and limits: an update and perspectives.

Heart transplantation, the gold standard treatment for end-stage heart failure, is limited by heart graft shortage, justifying expansion of the donor pool. Currently, static cold storage (SCS) of hearts from donations after brainstem death remains the standard practice, but it is usually limited to 240 min. Prolonged cold ischemia and ischemia-reperfusion injury (IRI) have been recognized as major causes of post-transplant graft failure. Continuous ex situ perfusion is a new approach for donor organ management to expand the donor pool and/or increase the utilization rate. Continuous ex situ machine perfusion (MP) can satisfy the metabolic needs of the myocardium, minimizing irreversible ischemic cell damage and cell death. Several hypothermic or normothermic MP methods have been developed and studied, particularly in the preclinical setting, but whether MP is superior to SCS remains controversial. Other approaches seem to be interesting for extending the pool of heart graft donors, such as blocking the paths of apoptosis and necrosis, extracellular vesicle therapy, or donor heart-specific gene therapy. In this systematic review, we summarize the mechanisms involved in IRI during heart transplantation and existing targeting therapies. We also critically evaluate all available data on continuous ex situ perfusion devices for adult donor hearts, highlighting its therapeutic potential and current limitations and shortcomings.

Case Report: Primary graft failure due to a reversed lenticule in Descemet Stripping Automated Endothelial Keratoplasty.

Introduction and importance: This report details the clinical features and management in a case of Descemet stripping automated endothelial keratoplasty (DSAEK) which had primary graft failure (PGF) due to an inverted yet attached lenticule. Presentation of case: A 66-year-old gentleman had poor visual recovery in the right eye after undergoing cataract surgery 12 years prior to presentation. The visual acuity was counting fingers and examination revealed endothelial decompensation. The patient underwent a DSAEK and postoperatively had a well attached lenticule. However, the cornea was edematous three weeks after the surgery and optical coherence tomography (OCT) revealed a reversed lenticule. The patient underwent a repeat DSAEK and had an uneventful postoperative course. The visual acuity was 20/40 after 7 months with a clear cornea and a well attached graft. Discussion: PGF is a rare complication following DSAEK which occurs due to poor endothelial function of the donor graft. Insertion of a reversed lenticule may get overlooked as a cause of PGF unless the graft edge profile is examined on an OCT scan. The graft in the current case was well attached despite its inverted position suggesting that graft adherence is perhaps not a function of the corneal endothelial pumps in isolation and may be driven by factors such as the intraocular pressure. Conclusion: A reversed DSAEK lenticule may have normal adherence to the host stroma and must be considered in cases with PGF. OCT of the graft edge is required for diagnosis before performing a repeat keratoplasty.

Donor-Specific Antibodies and Primary Graft Failure in Allogeneic Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis.

With the increasing number of non-matched donor hematopoietic stem cell transplantations (HSCTs) has come increasing evidence regarding factors affecting graft outcomes. One factor affecting graft outcomes currently being evaluated is anti-HLA donor-specific antibodies (DSAs). In this, we analyzed the clinical relevance of anti-HLA DSAs in patients who have undergone HSCT at a population level by conducting a systematic review of existing literature. A comprehensive search was conducted through PubMed, Embase, the Cochrane library, and Web of Science from inception to January 1, 2021. A meta-analysis was performed of the association between anti-HLA DSAs and primary graft failure (PGF) with further subgroup analyses. The search was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A total of 920 eligible citations were identified, out of which 15 studies were included in the final meta-analyses after application of rigorous selection criteria and independent review. A total of 2436 patients were included in these 15 studies. Patients with anti-HLA DSAs prior to undergoing HSCT had a 7.47-fold increased risk of PGF failure compared with patients without anti-HLA DSAs (odds ratio, 7.47; 95% confidence interval, 4.54 to 12.28, P < .001; I2= 28.91%, P = .1315). In subgroup and meta-regression analyses, area, Newcastle Ottawa Scale score, mean fluorescence intensity cutoff, primary disease, HSCT type, graft source, and pretransplantation desensitization did not affect the impact of anti-HLA DSAs on PGF. There also was no significant difference in impact between HLA class I and II on PGF. We conclude that the prior presence of anti-HLA DSAs has a negative impact on graft outcomes in recipients of haploidentical and umbilical cord blood HSCT.

Risk Factors for Severe Primary Graft Dysfunction in Infants Following Heart Transplant.

Background Previous studies suggest that infant heart transplant (HT) recipients are at higher risk of developing severe primary graft dysfunction (PGD) than older children. We sought to identify risk factors for developing severe PGD in infant HT recipients. Methods and Results We identified all HT recipients aged <1 year in the United States during 1996 to 2015 using the Organ Procurement and Transplant Network database. We linked their data to ELSO (Extracorporeal Life Support Organization) registry data to identify those with severe PGD, defined by initiation of extracorporeal membrane oxygenation support for PGD within 2 days following HT. We used multivariable logistic regression to assess risk factors for developing severe PGD. Of 1718 infants analyzed, 600 (35%) were <90 days old and 1079 (63%) had congenital heart disease. Overall, 134 (7.8%) developed severe PGD; 95 (71%) were initiated on extracorporeal membrane oxygenation support on the day of HT, 34 (25%) the next day, and 5 (4%) the following day. In adjusted analysis, recipient congenital heart disease, extracorporeal membrane oxygenation, or biventricular assist device support at transplant, recipient blood type AB, donor-recipient weight ratio <0.9, and graft ischemic time ≥4 hours were independently associated with developing severe PGD whereas left ventricular assist device support at HT was not. One-year graft survival was 48% in infants with severe PGD versus 87% without severe PGD. Conclusions Infant HT recipients with severe PGD have poor graft survival. Although some recipient-level risk factors are nonmodifiable, avoiding modifiable risk factors may mitigate further risk in infants at high risk of developing severe PGD.

Axillary artery cannulation for veno-arterial extracorporeal membrane oxygenation support in cardiogenic shock.

OBJECTIVE: To review the outcomes of axillary artery (AX) and femoral artery (FA) cannulation for veno-arterial extracorporeal membraneous oxygenation (VA-ECMO). METHODS: From 2009 to 2019, 371 patients who were supported with VA-ECMO for cardiogenic shock were compared based on the arterial cannulation site: AX (n = 218) versus FA (n = 153). RESULTS: Patients in the AX group were older (61 years vs 58 years, P = .011), had a greater prevalence of peripheral vascular disease (13.8% vs 5.2%, P = .008), and were less likely to have undergone cardiopulmonary resuscitation preoperatively (18.8% vs 36.6%, P < .001). Other characteristics were similar between groups, as were in-hospital outcomes, including survival to discharge (60.6% vs 56.9%), cerebrovascular accidents (12.4% vs 10.5%), cannulation-related bleeding (15.1% vs 17%), and length of VA-ECMO support (6 days). The incidence of leg ischemia (6.9% vs 15.7%, P = .006), limb ischemia related to VA-ECMO cannulation (0% vs 10.5%), the need to switch the cannulation site (4.6% vs 14.7%), and wound complications (WCs; 2.8% vs 15%) including infection and additional procedure were significantly greater in the FA group (P < .001). In multiple logistic regression analysis, FA cannulation and primary graft failure after heart transplantation were independent risk factors for cannulation-related WC. In subgroup analysis among patients with primary graft failure, WCs were more prevalent in FA cannulation (3.6% vs 39.1%, P = .001). CONCLUSIONS: AX cannulation for VA-ECMO is a safe and effective alternative to FA cannulation. It can be considered especially for patients with limited groin access, peripheral vascular disease, or for primary graft failure after heart transplant.