Knockdown of swine leukocyte antigen expression in porcine lung transplants enables graft survival without immunosuppression.

Immune rejection remains the major obstacle to long-term survival of allogeneic lung transplants. The expression of major histocompatibility complex molecules and minor histocompatibility antigens triggers allogeneic immune responses that can lead to allograft rejection. Transplant outcomes therefore depend on long-term immunosuppression, which is associated with severe side effects. To address this problem, we investigated the effect of genetically engineered transplants with permanently down-regulated swine leukocyte antigen (SLA) expression to prevent rejection in a porcine allogeneic lung transplantation (LTx) model. Minipig donor lungs with unmodified SLA expression (control group, n = 7) or with modified SLA expression (treatment group, n = 7) were used to evaluate the effects of SLA knockdown on allograft survival and on the nature and strength of immune responses after terminating an initial 4-week period of immunosuppression after LTx. Genetic engineering to down-regulate SLA expression was achieved during ex vivo lung perfusion by lentiviral transduction of short hairpin RNAs targeting mRNAs encoding ß2-microglobulin and class II transactivator. Whereas all grafts in the control group were rejected within 3 months, five of seven animals in the treatment group maintained graft survival without immunosuppression during the 2-year monitoring period. Compared with controls, SLA-silenced lung recipients had lower donor-specific antibodies and proinflammatory cytokine concentrations in the serum. Together, these data demonstrate a survival benefit of SLA-down-regulated lung transplants in the absence of immunosuppression.

Optimization of Enzymatic and Chemical Decellularization of Native Porcine Heart Valves for the Generation of Decellularized Xenografts.

One of the most important medical interventions for individuals with heart valvular disease is heart valve replacement, which is not without substantial challenges, particularly for pediatric patients. Due to their biological properties and biocompatibility, natural tissue-originated scaffolds derived from human or animal sources are one type of scaffold that is widely used in tissue engineering. However, they are known for their high potential for immunogenicity. Being free of cells and genetic material, decellularized xenografts, consequently, have low immunogenicity and, thus, are expected to be tolerated by the recipient's immune system. The scaffold ultrastructure and ECM composition can be affected by cell removal agents. Therefore, applying an appropriate method that preserves intact the structure of the ECM plays a critical role in the final result. So far, there has not been an effective decellularization technique that preserves the integrity of the heart valve's ultrastructure while securing the least amount of genetic material left. This study demonstrates a new protocol with untraceable cells and residual DNA, thereby maximally reducing any chance of immunogenicity. The mechanical and biochemical properties of the ECM resemble those of native heart valves. Results from this study strongly indicate that different critical factors, such as ionic detergent omission, the substitution of Triton X-100 with Tergitol, and using a lower concentration of trypsin and a higher concentration of DNase and RNase, play a significant role in maintaining intact the ultrastructure and function of the ECM.

Acute antiarrhythmic effects of SGLT2 inhibitors-dapagliflozin lowers the excitability of atrial cardiomyocytes.

In recent years, SGLT2 inhibitors have become an integral part of heart failure therapy, and several mechanisms contributing to cardiorenal protection have been identified. In this study, we place special emphasis on the atria and investigate acute electrophysiological effects of dapagliflozin to assess the antiarrhythmic potential of SGLT2 inhibitors. Direct electrophysiological effects of dapagliflozin were investigated in patch clamp experiments on isolated atrial cardiomyocytes. Acute treatment with elevated-dose dapagliflozin caused a significant reduction of the action potential inducibility, the amplitude and maximum upstroke velocity. The inhibitory effects were reproduced in human induced pluripotent stem cell-derived cardiomyocytes, and were more pronounced in atrial compared to ventricular cells. Hypothesizing that dapagliflozin directly affects the depolarization phase of atrial action potentials, we examined fast inward sodium currents in human atrial cardiomyocytes and found a significant decrease of peak sodium current densities by dapagliflozin, accompanied by a moderate inhibition of the transient outward potassium current. Translating these findings into a porcine large animal model, acute elevated-dose dapagliflozin treatment caused an atrial-dominant reduction of myocardial conduction velocity in vivo. This could be utilized for both, acute cardioversion of paroxysmal atrial fibrillation episodes and rhythm control of persistent atrial fibrillation. In this study, we show that dapagliflozin alters the excitability of atrial cardiomyocytes by direct inhibition of peak sodium currents. In vivo, dapagliflozin exerts antiarrhythmic effects, revealing a potential new additional role of SGLT2 inhibitors in the treatment of atrial arrhythmias.

Pericardial Closure With Expanded Polytetrafluoroethylene Patch in Left Ventricular Assist Device Surgery.

To reduce adhesions after left ventricular assist device (LVAD) implantation, pericardial closure using an expanded polytetrafluoroethylene (ePTFE) patch has been suggested. However, as foreign material, ePTFE patches could increase the risk of infectious complications. In this single-center retrospective study, we investigated outcomes of pericardial closure using an ePTFE patch in LVAD implantation. We included all patients who underwent LVAD implantation at our center between 2011 and 2020 (n = 166). Primary endpoint was development of mediastinitis at any point of time between LVAD implantation and heart transplantation (HTx) or death. Secondary endpoint was overall survival. Preoperative and postoperative clinical data were collected to ensure comparability between the groups. We included 166 patients with LVAD. A total of 116 patients (70%) underwent pericardial closure using an ePTFE patch. There were significant differences between the groups in treatment setting, previous cardiac surgery, Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) level, development of driveline infection, and HTx. Patients with an ePTFE patch developed mediastinitis more frequently (16%) than patients without ePTFE patch (4%) ( p = 0.039). A significant difference in overall survival between the groups could not be confirmed ( p = 0.29). The use of PTFE patches for pericardial closure in LVAD implantation was associated with a higher incidence of mediastinitis, but not with a difference in overall survival.

CD14highCD16+ monocytes are the main producers of Interleukin-10 following clinical heart transplantation.

Introduction: Following heart transplantation, a cascade of immunological responses is initiated influencing the clinical outcome and long-term survival of the transplanted patients. The anti-inflammatory cytokine interleukin-10 (IL-10) was shown to be elevated in the blood of heart transplant recipients directly after transplantation but the releasing cell populations and the composition of lymphocyte subsets following transplantation have not been thoroughly studied. Methods: We identified immune cells by immunophenotyping and analyzed intracellular IL-10 production in peripheral blood mononuclear cells (PBMC) of heart transplanted patients (n= 17) before, directly after and 24h post heart transplantation. The cells were stimulated with lipopolysaccharide or PMA/Ionomycin to enhance cytokine production within leukocytes in vitro. Results and discussion: We demonstrate that intermediate monocytes (CD14highCD16+), but not CD8+ T cells, CD4+ T cells, CD56+ NK cells or CD20+ B cells appeared to be the major IL-10 producers within patients PBMC following heart transplantation. Consequently, the absolute monocyte count and the ratio of intermediate monocytes to classical monocytes (CD14+CD16-) were specifically increased in comparison to pre transplant levels. Hence, this population of monocytes, which has not been in the focus of heart transplantation so far, may be an important modulator of clinical outcome and long-term survival of heart transplant recipients. Alteration of blood-circulating monocytes towards a CD14highCD16+ phenotype could therefore shift the pro-inflammatory immune response towards induction of graft tolerance, and may pave the way for the optimization of immunosuppression.

Activation of neurokinin-III receptors modulates human atrial TASK-1 currents.

RATIONALE: The neurokinin-III receptor was recently shown to regulate atrial cardiomyocyte excitability by inhibiting atrial background potassium currents. TASK-1 (hK2P3.1) two-pore-domain potassium channels, which are expressed atrial-specifically in the human heart, contribute significantly to atrial background potassium currents. As TASK-1 channels are regulated by a variety of intracellular signalling cascades, they represent a promising candidate for mediating the electrophysiological effects of the Gq-coupled neurokinin-III receptor. OBJECTIVE: To investigate whether TASK-1 channels mediate the neurokinin-III receptor activation induced effects on atrial electrophysiology. METHODS AND RESULTS: In Xenopus laevis oocytes, heterologously expressing neurokinin-III receptor and TASK-1, administration of the endogenous neurokinin-III receptor ligands substance P or neurokinin B resulted in a strong TASK-1 current inhibition. This could be reproduced by application of the high affinity neurokinin-III receptor agonist senktide. Moreover, preincubation with the neurokinin-III receptor antagonist osanetant blunted the effect of senktide. Mutagenesis studies employing TASK-1 channel constructs which lack either protein kinase C (PKC) phosphorylation sites or the domain which is regulating the diacyl glycerol (DAG) sensitivity domain of TASK-1 revealed a protein kinase C independent mechanism of TASK-1 current inhibition: upon neurokinin-III receptor activation TASK-1 channels are blocked in a DAG-dependent fashion. Finally, effects of senktide on atrial TASK-1 currents could be reproduced in patch-clamp measurements, performed on isolated human atrial cardiomyocytes. CONCLUSIONS: Heterologously expressed human TASK-1 channels are inhibited by neurokinin-III receptor activation in a DAG dependent fashion. Patch-clamp measurements, performed on human atrial cardiomyocytes suggest that the atrial-specific effects of neurokinin-III receptor activation on cardiac excitability are predominantly mediated via TASK-1 currents.

Temporary circulatory support with surgically implanted microaxial pumps in postcardiotomy cardiogenic shock following coronary artery bypass surgery.

Objectives: Patients with ischemic cardiomyopathy undergoing coronary artery bypass grafting (CABG) surgery may develop postcardiotomy cardiogenic shock. In these cases, implantation of an Impella 5.0 or 5.5 microaxial pump offers full hemodynamic support while simultaneously unloading of the left ventricle. Methods: Preoperative, perioperative, and postoperative data of all patients receiving postoperative support with an Impella 5.0 or 5.5 after CABG surgery between September 2017 and October 2022 were retrospectively collected. Cohort built-up was performed according to the timing of Impella implantation, either simultaneous during CABG surgery or delayed. Results: A total of n = 42 patients received postoperative Impella support, of whom 27 patients underwent simultaneous Impella implantation during CABG surgery and 15 patients underwent delayed Impella therapy. Preoperative left ventricular ejection fraction was similarly low in both groups (26.7 ± 0.7% vs 24.8 ± 11.3%; P = .32). In the delayed cohort, Impella implantation was performed after a median of 1 (1; 2) days after CABG surgery. Survival after 30 days (75.6% vs 47.6%, P = .04) and 1 year (69.4% vs 29.8%, P = .03) was better in the cohort receiving simultaneous Impella implantation. Conclusions: The combined advantages of hemodynamic support and LV unloading with microaxial pumps may lead to a favorable survival in patients with left ventricular failure following CABG surgery. Early implantation during the initial surgery shows a trend toward a more favorable survival as compared with patients receiving delayed support.

Temporary Mechanical Circulatory Support in Cardiogenic Shock Patients after Cardiac Procedures: Selection Algorithm and Weaning Strategies.

Mechanical circulatory support has proven effective in managing postcardiotomy cardiogenic shock by stabilizing patients' hemodynamics and ensuring adequate organ perfusion. Among the available device modalities, the combination of extracorporeal life support and a microaxial flow pump for left ventricular unloading has emerged as a valuable tool in the surgical armamentarium. In this publication, we provide recommendations for the application and weaning of temporary mechanical circulatory support in cardiogenic shock patients, derived from a consensus among leading cardiac centers in German-speaking countries.

Heart Transplantation in High-Risk Recipients Employing Donor Marginal Grafts Preserved With Ex-Vivo Perfusion.

Extending selection criteria to face donor organ shortage in heart transplantation (HTx) may increase the risk of mortality. Ex-vivo normothermic perfusion (EVP) limits ischemic time allowing assessment of graft function. We investigated the outcome of HTx in 80 high-risk recipients transplanted with marginal donor and EVP-preserved grafts, from 2016 to 2021. The recipients median age was 57 years (range, 13-75), with chronic renal failure in 61%, impaired liver function in 11% and previous cardiac surgery in 90%; 80% were mechanically supported. Median RADIAL score was 3. Mean graft ischemic time was 118 ± 25 min, "out-of-body" time 420 ± 66 min and median cardiopulmonary bypass (CPB) time 228 min (126-416). In-hospital mortality was 11% and ≥moderate primary graft dysfunction 16%. At univariable analysis, CPB time and high central venous pressure were risk factors for mortality. Actuarial survival at 1 and 3 years was 83% ± 4%, and 72% ± 7%, with a median follow-up of 16 months (range 2-43). Recipient and donor ages, pre-HTx extracorporeal life support and intra-aortic balloon pump were risk factors for late mortality. In conclusion, the use of EVP allows extension of the graft pool by recruitment of marginal donors to successfully perform HTx even in high-risk recipients.

Oral Anticoagulants after Heart Transplantation-Comparison between Vitamin K Antagonists and Direct Oral Anticoagulants.

AIMS: Patients after heart transplantation (HTX) often require oral anticoagulants (OACs) due to atrial arrhythmias or thromboembolic events but little is known about the post-transplant use of direct oral anticoagulants (DOACs). We investigated the frequency, indications, and complications of DOACs and vitamin K antagonists (VKAs) after HTX. METHODS: We screened all adult patients for the use of post-transplant OACs who underwent HTX at Heidelberg Heart Center between 2000 and 2021. Patients were stratified by type of OAC (DOAC or VKA) and by DOAC agents (apixaban, dabigatran, edoxaban, or rivaroxaban). Indications for OACs comprised atrial fibrillation, atrial flutter, pulmonary embolism, upper and lower extremity deep vein thrombosis, as well as intracardiac thrombus. RESULTS: A total of 115 of 459 HTX recipients (25.1%) required OACs, including 60 patients with DOACs (52.2%) and 55 patients with VKAs (47.8%). Concerning DOACs, 28 patients were treated with rivaroxaban (46.7%), 27 patients with apixaban (45.0%), and 5 patients with edoxaban (8.3%). We found no significant differences between both groups concerning demographics, immunosuppressive drugs, concomitant medications, indications for OACs, ischemic stroke, thromboembolic events, or OAC-related death. Patients with DOACs after HTX had a significantly lower one-year rate of overall bleeding complications (p = 0.002) and a significantly lower one-year rate of gastrointestinal hemorrhage (p = 0.011) compared to patients with VKAs after HTX in the Kaplan-Meier estimator. CONCLUSIONS: DOACs were comparable to VKAs concerning the risk of ischemic stroke, thromboembolic events, or OAC-related death but were associated with significantly fewer bleeding complications in HTX recipients.

Bilateral lung transplantation for pediatric pulmonary arterial hypertension: perioperative management and one-year follow-up.

Background: Bilateral lung transplantation (LuTx) remains the only established treatment for children with end-stage pulmonary arterial hypertension (PAH). Although PAH is the second most common indication for LuTx, little is known about optimal perioperative management and midterm clinical outcomes. Methods: Prospective observational study on consecutive children with PAH who underwent LuTx with scheduled postoperative VA-ECMO support at Hannover Medical School from December 2013 to June 2020. Results: Twelve patients with PAH underwent LuTx (mean age 11.9 years; age range 1.9-17.8). Underlying diagnoses included idiopathic (n = 4) or heritable PAH (n = 4), PAH associated with congenital heart disease (n = 2), pulmonary veno-occlusive disease (n = 1), and pulmonary capillary hemangiomatosis (n = 1). The mean waiting time was 58.5 days (range 1-220d). Three patients were bridged to LuTx on VA-ECMO. Intraoperative VA-ECMO/cardiopulmonary bypass was applied and VA-ECMO was continued postoperatively in all patients (mean ECMO-duration 185 h; range 73-363 h; early extubation). The median postoperative ventilation time was 28 h (range 17-145 h). Echocardiographic conventional and strain analysis showed that 12 months after LuTx, all patients had normal biventricular systolic function. All PAH patients are alive 2 years after LuTx (median follow-up 53 months, range 26-104 months). Conclusion: LuTx in children with end-stage PAH resulted in excellent midterm outcomes (100% survival 2 years post-LuTx). Postoperative VA-ECMO facilitates early extubation with rapid gain of allograft function and sustained biventricular reverse-remodeling and systolic function after RV pressure unloading and LV volume loading.

Lungs From Donors ≥70 Years of Age for Transplantation-Do Long-Term Outcomes Justify Their Use?

Donor shortages have led transplant centers to extend their criteria for lung donors. Accepting lung donors ≥70 years of age has previously shown good short-term outcomes; however, no mid- and long-term outcome data on these extended criteria donors has been published to date. In this study, all patients who underwent lung transplantation between 06/2010 and 12/2019 were included in the analysis, and the outcomes were compared between patients receiving organs from donors <70 years of age and patients transplanted with lungs from donors ≥70 years of age. Among the 1,168 lung-transplanted patients, 62 patients received lungs from donors ≥70 years of age. The recipient age of those receiving older organs was significantly higher, and they were more likely to suffer from obstructive lung disease. Older donors were exposed to significantly shorter periods of mechanical ventilation prior to donation, had higher Horowitz indices, and were less likely to have smoked. The postoperative time on mechanical ventilation, time on ICU, and total hospital stay were comparable. The overall survival as well as CLAD-free survival showed no differences between both groups in the follow-up period. Utilization of lungs from donors ≥70 years of age leads to excellent mid- and long-term results that are similar to organs from younger donors when the organs from older donors are carefully preselected.

Lung transplantation despite preformed donor-specific antihuman leukocyte antigen antibodies: a 9-year single-center experience.

Pretransplant allosensitization to human leukocyte antigens (HLA) increases the recipient's waiting list time and mortality in lung transplantation. Rather than waiting for crossmatch-negative donors, since 2013, recipients with preformed donor-specific antiHLA antibodies (pfDSA) have been managed with repeated IgA- and IgM-enriched intravenous immunoglobulin (IgGAM) infusions, usually in combination with plasmapheresis before IgGAM and a single dose of antiCD20 antibody. This retrospective study presents our 9-year experience with patients transplanted with pfDSA. Records of patients transplanted between February 2013 and May 2022 were reviewed. Outcomes were compared between patients with pfDSA and those without any de novo donor-specific antiHLA antibodies. The median follow-up time was 50 months. Of the 1,043 patients who had undergone lung transplantation, 758 (72.7%) did not develop any early donor-specific antiHLA antibodies, and 62 (5.9%) patients exhibited pfDSA. Among the 52 (84%) patients who completed treatment, pfDSA was cleared in 38 (73%). In pfDSA vs control patients and at 8-year follow-up, respectively, graft survival (%) was 75 vs 65 (P = .493) and freedom from chronic lung allograft dysfunction (%) was 63 vs 65 (P = .525). In lung transplantation, crossing the preformed HLA-antibody barrier is safe using a treatment protocol based on IgGAM. Patients with pfDSA have a good 8-year graft survival rate and freedom from chronic lung allograft dysfunction, similar to control patients.

Impact of total ischaemic time and disease severity class on graft function after bilateral lung transplantation.

OBJECTIVES: Total ischaemic time (IT) is considered a limiting factor in lung transplantation. In this retrospective study, we investigate effects of IT and disease burden on outcomes after bilateral lung transplantation. METHODS: A total of 1298 patients undergoing bilateral lung transplantation between January 2010 and May 2022 (follow-up 100%, median 54 months) were included. Pre-transplant diseases' severity (recipient body mass index, recipient age, previous lung transplantation, Tacrolimus immunosuppression, preoperative recipient extracorporeal membrane oxygenation support, lung volume reduction) for graft failure was individually calculated and-as IT-categorized. Vice versa adjusted Cox models were calculated. Considering competing risks, we assessed cumulative incidences of airway obstructive complications and chronic lung allograft dysfunction with death as competing risk factors for primary graft dysfunction were assessed by binary logistic regression. RESULTS: Higher disease burden significantly accelerated chronic lung allograft dysfunction and death occurrence (P < 0.001); IT did not. IT-adjusted disease burden strata showed 50% graft survival differences at 11 years after transplantation (range 24-74%), disease burden-adjusted IT strata 18% for all and 6% (54-60%) among those above 7 h. All significant primary graft dysfunction risk factors were diagnoses related, IT was not significantly important and odds ratios did not increase with IT. CONCLUSIONS: The eventual graft survival disadvantage that results from an IT between 7 and at least 11 h is negligible in contrast to frequent recipients' disease-based risk levels.

Immediate major dynamic changes in the T- and NK-cell subset composition after cardiac transplantation.

Early kinetics of lymphocyte subsets involved in tolerance and rejection following heart transplantation (HTx) are barely defined. Here, we aimed to delineate the early alloimmune response immediately after HTx. Therefore, blood samples from 23 heart-transplanted patients were collected before (pre-), immediately (T0), 24 hours (T24), and 3 weeks (3 wks) after HTx. Immunophenotyping was performed using flow cytometry. A significant increase was detected for terminally differentiated (TEMRA) CD4+ or CD8+ T cells and CD56dim CD16+ NK cells immediately after HTx linked to a decrease in naïve CD8+ and CM CD4+ T as well as CD56bright CD16- NK cells, returning to baseline levels at T24. More detailed analyses revealed increased CD69+ CD25- and diminished CD69- CD25- CD4+ or CD8+ T-cell proportions at T0 associated with decreasing S1PR1 expression. Passenger T and NK cells were found at low frequencies only in several patients at T0 and did not correlate with lymphocyte alterations. Collectively, these results suggest an immediate, transient shift toward memory T and NK cells following HTx. Opposite migratory properties of naïve versus memory T and NK cells occurring in the early phase after HTx could underlie these observations and may impinge on the development of allo-specific immune responses.

Influence of Tricuspid Regurgitation After Heart Transplantation: A Single-center Experience.

Tricuspid valve regurgitation (TVR) is often observed after orthotopic heart transplantation. However, there is a scarcity of data regarding long-term outcomes of patients with TVR. Methods: Between January 2008 and December 2015, 169 patients underwent orthotopic heart transplantation at our center and were included in this study. TVR trends and associated clinical parameters were retrospectively analyzed. TVR was assessed after 30 d, 1 y, 3 y, and 5 y, and groups were defined according to changes in TVR grade: constant (group 1; n = 100), improvement (group 2; n = 26), and deterioration (group 3; n = 43). Survival, outcome with regard to operative technique, and long-term kidney and liver function during follow-up were assessed. Results: Mean follow-up time was 7.67 ± 4.17 y (median 8.62, Q1 5.06, Q3 11.16). Overall mortality was 42.0%, with differences between the groups (P < 0.01). Cox regression analysis revealed improvement of TVR as a significant predictor for survival (hazard ratio 0.23; 95% confidence interval, 0.08-0.63, P < 0.01). After 1 y 2.7%, after 3 y 3.7%, and after 5 y 3.9% of the patients showed persistent severe TVR. Creatinine levels after 30 d and 1, 3, and 5 y showed significant differences between the groups (P = 0.02, P < 0.01, P < 0.01, and P = 0.01), deterioration of TVR being associated with higher creatinine levels during follow-up. Conclusions: Deterioration of TVR is associated with higher mortality and renal dysfunction. Improvement of TVR may function as a positive predictor for long-term survival after heart transplantation. Improvement of TVR should be a therapeutic goal offering a prognostic value for long-term survival.

Surgical management of large tracheoesophageal fistula in infants after button battery ingestion.

OBJECTIVES: In recent years, an increase in severe and even fatal outcomes related to oesophageal or airway button battery (BB) ingestion by infants and small children has been reported. Extensive tissue necrosis caused by lodged BB can lead to major complications, including tracheoesophageal fistula (TEF). In these instances, best treatment remains controversial. While small defects may warrant a conservative approach, surgery often remains inevitable in highly complex cases with large TEF. We present a series of small children that underwent successful surgical management by a multidisciplinary team in our institution. METHODS: This is a retrospective analysis of n = 4 patients <18 months undergoing TEF repair from 2018 to 2021. RESULTS: Surgical repair under extracorporeal membrane oxygenation (ECMO) support was feasible in n = 4 patients by reconstructing the trachea with decellularized aortic homografts that were buttressed with pedicled latissimus dorsi muscle flaps. While direct oesophageal repair was feasible in 1 patient, 3 required esophagogastrostomy and secondary repair. The procedure was completed successfully in all 4 children with no mortality and acceptable morbidity. CONCLUSIONS: Tracheo-oesophageal repair after BB ingestion remains challenging and is associated with major morbidity. Bioprosthetic materials in conjunction with the interposition of vascularized tissue flaps between trachea and oesophagus appear to be a valid approach to manage severe cases.

Does donor-recipient age mismatch have an influence on outcome after lung transplantation? A single-centre experience.

OBJECTIVES: Lack of organ donors demands transplantation of older lung allografts for recipients between 0 and 50 years. So far, it has not yet been investigated whether donor-recipient age mismatch affects long-term outcome. METHODS: Records of patients aged between 0 and 50 years were retrospectively reviewed. Donor-recipient age mismatch was calculated subtracting recipient age from donor age. Multivariable Cox regression analyses was performed to assess donor-recipient age mismatch regarding the end points' overall patient mortality, mortality conditioned to hospital discharge, biopsy-confirmed rejection and chronic lung allograft dysfunction. Furthermore, we performed competing risk analysis to analyse if age mismatch affects biopsy-confirmed rejection and CLAD while death being a competing risk. RESULTS: Between January 2010 and September 2021, out of 1363 patients who underwent lung transplantation at our institution, 409 patients fulfilled the eligibility criteria and were included. Age mismatch ranged between 0 and 56 years. Multivariable analysis revealed that donor-recipient age mismatch does not affect overall patient mortality (P = 0.19), biopsy-confirmed rejection (P = 0.68) and chronic lung allograft dysfunction (P = 0.42). There was no difference seen in CLAD (P = 0.166) and biopsy-confirmed rejection (P = 0.944) with the competing risk death (P = 0.765 and P = 0.851; respectively). CONCLUSIONS: Age mismatch between recipients and donors of lung allografts does not affect long-term outcomes after lung transplantation.

Outcomes in patients with cardiac amyloidosis undergoing heart transplantation: the eurotransplant experience.

BACKGROUND: When advanced heart failure occurs in cardiac amyloidosis, prognosis is poor. In this setting heart transplantation (HTX) is a treatment option for selected patients. We here present the results of post-transplantation outcomes in cardiac amyloidosis within the Eurotransplant area, investigating possible predictors of survival. METHODS: Of 115 patients undergoing HTX due to cardiac amyloidosis in the Eurotransplant region between November 1987 and May 2020, detailed assessment prior to transplantation was available in 85 patients. The present study was conducted in a retrospective approach. Primary endpoint was mortality after HTX. Baseline variables were entered in a Cox proportional hazards model with the primary endpoint as a dependent variable. RESULTS: Median overall survival following HTX was 6.3 years in the overall collective and the subgroup. Univariate Cox proportional hazards model revealed a significant relationship between overall survival and the transplantation period (2008 to 2020 vs 1987 to 2007; median survival 9.7 years vs 1.8 years, hazard ratio 0.45, p = 0.01). Further predictors were albumin concentration (hazard ratio 0.92, p < 0.001), and systolic blood pressure (hazard ratio 0.96, p < 0.001). The transplant period as well as albumin concentration remained significant independent predictors in the AL sub cohort in a multivariate Cox proportional hazards model. CONCLUSIONS: HTX is a viable treatment option for patients at an advanced stage of cardiac amyloidosis as overall survival after transplantation has improved in the modern age. Patients at a very advanced stage of the disease, indicated by low serum albumin and blood pressure, show worse outcomes following HTX. Optimal timing and careful patient selection may therefore be particularly important to further improve post-HTX survival in amyloidosis patients.