Hypoimmune induced pluripotent stem cell-derived cell therapeutics treat cardiovascular and pulmonary diseases in immunocompetent allogeneic mice.

The emerging field of regenerative cell therapy is still limited by the few cell types that can reliably be differentiated from pluripotent stem cells and by the immune hurdle of commercially scalable allogeneic cell therapeutics. Here, we show that gene-edited, immune-evasive cell grafts can survive and successfully treat diseases in immunocompetent, fully allogeneic recipients. Transplanted endothelial cells improved perfusion and increased the likelihood of limb preservation in mice with critical limb ischemia. Endothelial cell grafts transduced to express a transgene for alpha1-antitrypsin (A1AT) successfully restored physiologic A1AT serum levels in mice with genetic A1AT deficiency. This cell therapy prevented both structural and functional changes of emphysematous lung disease. A mixture of endothelial cells and cardiomyocytes was injected into infarcted mouse hearts, and both cell types orthotopically engrafted in the ischemic areas. Cell therapy led to an improvement in invasive hemodynamic heart failure parameters. Our study supports the development of hypoimmune, universal regenerative cell therapeutics for cost-effective treatments of major diseases.

Morbidity and Mortality Associated With Blood Transfusions in Elective Adult Cardiac Surgery.

OBJECTIVES: Perioperative transfusion thresholds have garnered increasing scrutiny as restrictive strategies have been shown to be noninferior. The study authors used data from a statewide academic collaborative to test the association between transfusion and 30-day mortality. DESIGN: All adult patients undergoing coronary artery bypass grafting (CABG) and/or valve surgeries between 2013 and 2019 in the authors' Academic Cardiac Surgery Consortium were examined. The relationship between the number of overall packed red blood cell (pRBC) and coagulation product (CP) (fresh frozen plasma, cryoprecipitate, platelets) transfusions on 30-day mortality was evaluated. Multivariate regression was used to evaluate predictors of transfusion and study endpoints. Machine learning (ML) models also were developed to predict 30-day mortality and rank transfusion-related features by relative importance. SETTING: At an Academic Cardiac Surgery Consortium of 5 institutions. PARTICIPANTS: Patients ≥18 years old undergoing CABG and/or valve surgeries. MEASUREMENTS AND MAIN RESULTS: Of the 7,762 patients (median hematocrit [HCT] 39%, IQR 35%-43%) who were included in the final study cohort, >40% were transfused at least 1 unit of pRBC or CP. In adjusted analyses, higher preoperative HCT was associated with reduced odds of mortality (adjusted odds ratio [aOR] 0.95, 95% CI 0.92-0.98), renal failure (aOR 0.95, 95% CI 0.92-0.98), and prolonged mechanical ventilation (aOR 0.97, 95% CI 0.95-0.99). In contrast, perioperative transfusions were associated with increased 30-day mortality after adjustment for preoperative HCT and other baseline features. The ML models were able to predict 30-day mortality with an area under the curve of 0.814-to-0.850, with perioperative transfusions displaying the highest feature importance. CONCLUSIONS: The present analysis found increasing HCT to be associated with a lower incidence of mortality. The study authors also found a direct dose-response association between transfusions and all study endpoints examined.

Outcomes of transcatheter aortic valve replacement in end stage liver and renal disease.

OBJECTIVES: This study evaluates in-hospital, 30-day, and 1-year outcomes post-transcatheter aortic valve replacement (TAVR) in end stage liver disease (ESLD) and/or end stage renal disease (ESRD) compared with patients without these comorbidities. BACKGROUND: TAVR is an alternative to surgical aortic valve replacement in patients with ESLD and ESRD, though current outcomes data are limited. METHODS: We compared 309 patients (N = 29 ESLD and/or ESRD, N = 280 control) age > 18 who underwent transfemoral TAVR from 2014 to 2020 have been compared. RESULTS: Patients with ESLD and ESRD were younger (69.9 ± 11.7 vs. 79.1 ± 9.8, p < .01) with higher STS-PROM scores (8.1 ± 6.7 vs. 4.6 ± 3.9, p < .01). ESRD and ESLD patients had similar rates of in-hospital major vascular complications (3.4% vs. 3.2%, p = .96), major bleeding events (3.4% vs. 3.2%, p = .95), and mortality (0.0% vs. 1.8%, p = .47). Mortality rates were similar at 30-days (3.4% vs. 2.1%, p = .65) with trend to higher mortality at 6-months (6.9% vs. 3.2%, p = .31) and 1-year (15.4% vs. 7.0%, p = .13). Readmission rates were higher in the ESLD and ESRD cohort at 6-months (53.2% vs. 28.6%, p < .01) and 1-year (65.4% vs. 41.0%, p = .02). One patient received dual kidney-liver transplant, 1 patient received a liver transplant, and 7 additional patients were listed for transplant. CONCLUSION: Patients with ESLD and/or ESRD who underwent TAVR had similar mortality at discharge and 30-days compared with patients without these comorbidities with a trend toward increased mortality at 1-year. This study suggests that TAVR is an option for aortic valve disease patients with ESRD and/or ESLD in order to remove cardiac barriers to liver or kidney transplant.

Frailty after lung transplantation is associated with impaired health-related quality of life and mortality.

BACKGROUND: Lung transplantation and related medications are associated with pathobiological changes that can induce frailty, a state of decreased physiological reserve. Causes of persistent or emergent frailty after lung transplantation, and whether such transplant-related frailty is associated with key outcomes, are unknown. METHODS: Frailty and health-related quality of life (HRQL) were prospectively measured repeatedly for up to 3 years after lung transplantation. Frailty, quantified by the Short Physical Performance Battery (SPPB), was tested as a time-dependent binary and continuous predictor. The association of transplant-related frailty with HRQL and mortality was evaluated using mixed effects and Cox regression models, respectively, adjusting for age, sex, ethnicity, diagnosis, and for body mass index and lung function as time-dependent covariates. We tested the association between measures of body composition, malnutrition, renal dysfunction and immunosuppressants on the development of frailty using mixed effects models with time-dependent predictors and lagged frailty outcomes. RESULTS: Among 259 adults (56% male; mean age 55.9±12.3 years), transplant-related frailty was associated with lower HRQL. Frailty was also associated with a 2.5-fold higher mortality risk (HR 2.51; 95% CI 1.21 to 5.23). Further, each 1-point worsening in SPPB was associated, on average, with a 13% higher mortality risk (HR 1.13; 95% CI 1.04 to 1.23). Secondarily, we found that sarcopenia, underweight and obesity, malnutrition, and renal dysfunction were associated with the development of frailty after transplant. CONCLUSIONS: Transplant-related frailty is associated with lower HRQL and higher mortality in lung recipients. Abnormal body composition, malnutrition and renal dysfunction may contribute to the development of frailty after transplant. Confirming the role of these potential contributors and developing interventions to mitigate frailty may improve lung transplant success.

Impact of donor lung quality on post-transplant recipient outcome in the Lung Allocation Score era in Eurotransplant - a historical prospective study.

The aim of this study was to investigate whether there is an impact of donation rates on the quality of lungs used for transplantation and whether donor lung quality affects post-transplant outcome in the current Lung Allocation Score era. All consecutive adult LTx performed in Eurotransplant (ET) between January 2012 and December 2016 were included (N = 3053). Donors used for LTx in countries with high donation rate were younger (42% vs. 33% ≤45 years, P < 0.0001), were less often smokers (35% vs. 46%, P < 0.0001), had more often clear chest X-rays (82% vs. 72%, P < 0.0001), had better donor oxygenation ratios (20% vs. 26% with PaO2 /FiO2  ≤ 300 mmHg, P < 0.0001), and had better lung donor score values (LDS; 28% vs. 17% with LDS = 6, P < 0.0001) compared with donors used for LTx in countries with low donation rate. Survival rates for the groups LDS = 6 and ≥7 at 5 years were 69.7% and 60.9% (P = 0.007). Lung donor quality significantly impacts on long-term patient survival. Countries with a low donation rate are more oriented to using donor lungs with a lesser quality compared to countries with a high donation rate. Instead of further stretching donor eligibility criteria, the full potential of the donor pool should be realized.

Dichloroacetate prevents restenosis in preclinical animal models of vessel injury.

Despite the introduction of antiproliferative drug-eluting stents, coronary heart disease remains the leading cause of death in the United States. In-stent restenosis and bypass graft failure are characterized by excessive smooth muscle cell (SMC) proliferation and concomitant myointima formation with luminal obliteration. Here we show that during the development of myointimal hyperplasia in human arteries, SMCs show hyperpolarization of their mitochondrial membrane potential (ΔΨm) and acquire a temporary state with a high proliferative rate and resistance to apoptosis. Pyruvate dehydrogenase kinase isoform 2 (PDK2) was identified as a key regulatory protein, and its activation proved necessary for relevant myointima formation. Pharmacologic PDK2 blockade with dichloroacetate or lentiviral PDK2 knockdown prevented ΔΨm hyperpolarization, facilitated apoptosis and reduced myointima formation in injured human mammary and coronary arteries, rat aortas, rabbit iliac arteries and swine (pig) coronary arteries. In contrast to several commonly used antiproliferative drugs, dichloroacetate did not prevent vessel re-endothelialization. Targeting myointimal ΔΨm and alleviating apoptosis resistance is a novel strategy for the prevention of proliferative vascular diseases.

Lung allocation score: the Eurotransplant model versus the revised US model - a cross-sectional study.

Both Eurotransplant (ET) and the US use the lung allocation score (LAS) to allocate donor lungs. In 2015, the US implemented a new algorithm for calculating the score while ET has fine-tuned the original model using business rules. A comparison of both models in a contemporary patient cohort was performed. The rank positions and the correlation between both scores were calculated for all patients on the active waiting list in ET. On February 6th 2017, 581 patients were actively listed on the lung transplant waiting list. The median LAS values were 32.56 and 32.70 in ET and the US, respectively. The overall correlation coefficient between both scores was 0.71. Forty-three per cent of the patients had a < 2 point change in their LAS. US LAS was more than two points lower for 41% and more than two points higher for 16% of the patients. Median ranks and the 90th percentiles for all diagnosis groups did not differ between both scores. Implementing the 2015 US LAS model would not significantly alter the current waiting list in ET.

Thalidomide treatment prevents chronic graft rejection after aortic transplantation in rats - an experimental study.

Cardiac allograft vasculopathy (CAV) affects approximately 30% of cardiac transplant patients at 5 years post-transplantation. To date, there are few CAV treatment or prevention options, none of which are highly effective. The aim of the study was to investigate the effect of thalidomide on the development of CAV. The effect of thalidomide treatment on chronic rejection was assessed in rat orthotopic aortic transplants in allogeneic F344 or syngeneic Lew rats (n = 6 per group). Animals were left untreated or received thalidomide for 30 days post-transplant, and evidence of graft CAV was determined by histology (trichrome and immunohistochemistry) and intragraft cytokine measurements. Animals that received thalidomide treatment post-transplant showed markedly reduced luminal obliteration, with concomitant rescue of smooth muscle cells (SMCs) in the aortic media of grafts. Thalidomide counteracted neointimal hyperplasia by preventing dedifferentiation of vascular SMCs. Measurement of intragraft cytokine levels after thalidomide treatment revealed downregulation of matrix metalloproteinase 8 and monocyte chemotactic protein 1, cytokines involved in tissue remodelling and inflammation, respectively. Importantly, no negative side effects of thalidomide were observed. Thalidomide treatment prevents CAV development in a rodent model and is therefore potentially useful in clinical applications to prevent post-transplant heart rejection.

Local MicroRNA Modulation Using a Novel Anti-miR-21-Eluting Stent Effectively Prevents Experimental In-Stent Restenosis.

OBJECTIVE: Despite advances in stent technology for vascular interventions, in-stent restenosis (ISR) because of myointimal hyperplasia remains a major complication. APPROACH AND RESULTS: We investigated the regulatory role of microRNAs in myointimal hyperplasia/ISR, using a humanized animal model in which balloon-injured human internal mammary arteries with or without stenting were transplanted into Rowett nude rats, followed by microRNA profiling. miR-21 was the only significantly upregulated candidate. In addition, miR-21 expression was increased in human tissue samples from patients with ISR compared with coronary artery disease specimen. We systemically repressed miR-21 via intravenous fluorescein-tagged-locked nucleic acid-anti-miR-21 (anti-21) in our humanized myointimal hyperplasia model. As expected, suppression of vascular miR-21 correlated dose dependently with reduced luminal obliteration. Furthermore, anti-21 did not impede reendothelialization. However, systemic anti-miR-21 had substantial off-target effects, lowering miR-21 expression in liver, heart, lung, and kidney with concomitant increase in serum creatinine levels. We therefore assessed the feasibility of local miR-21 suppression using anti-21-coated stents. Compared with bare-metal stents, anti-21-coated stents effectively reduced ISR, whereas no significant off-target effects could be observed. CONCLUSION: This study demonstrates the efficacy of an anti-miR-coated stent for the reduction of ISR.

Orthotopic tracheal transplantation using human bronchus: an original xenotransplant model of obliterative airway disorder.

Bronchiolitis obliterans syndrome (BOS) is a main cause of allograft dysfunction and mortality after lung transplantation (LTx). A better understanding of BOS pathogenesis is needed to overcome this treatment-refractory complication. Orthotopic tracheal transplantation using human bronchus was performed in Brown Norway (BN) and nude (RNU) rats. Allografts were recovered in both strains at Day 7 (BN7 , n = 6; RNU7 , n = 7) or Day 28 (BN28 , n = 6; RNU28 , n = 6). Immune response of the host against the bronchial graft was assessed. Human samples from BOS patients were used to compare with the histological features of the animal model. Obstruction of the allograft lumen associated with significant infiltration of CD3+ and CD68+ cells was observed in the BN group on Day 28. Immune response from type 1 T-helper cells against the tracheal xenograft was higher in BN animals compared to nude animals on Days 7 and 28 (P < 0.001 and P = 0.035). Xenoreactive antibodies were significantly higher at Day 7 (IgM) and Day 28 (IgG) in the BN group compared to RNU (respectively, 37.6 ± 6.5 vs. 5.8 ± 0.7 mean fluorescence, P = 0.039; and 22.4 ± 3.8 vs. 6.9 ± 1.6 mean fluorescence, P = 0.011). Immunocompetent animals showed a higher infiltration of S100A4+ cells inside the bronchial wall after 28 days, associated with cartilage damage ranging from invasion to complete destruction. In vitro expression of S100A4 by human fibroblasts was higher when stimulated by mononuclear cells (MNCs) from BN rats than from RNU (2.9 ± 0.1 vs. 2.4 ± 0.1 mean fluorescence intensity, P = 0.005). Similarly, S100A4 was highly expressed in response to human MNCs compared to stimulation by T-cell-depleted human MNCs (4.3 ± 0.2 vs. 2.7 ± 0.1 mean fluorescence intensity, P < 0.001). Obliterative bronchiolitis has been induced in a new xenotransplant model in which chronic airway obstruction was associated with immune activation against the xenograft. Cartilage infiltration by S100A4+ cells might be stimulated by T cells.

Thymoglobulin induction in heart transplantation: patient selection and implications for maintenance immunosuppression.

Clinical data relating to rabbit antithymocyte globulin (rATG) induction in heart transplantation are far less extensive than for other immunosuppressants, or indeed for rATG in other indications. This was highlighted by the low grade of evidence and the lack of detailed recommendations for prescribing rATG in the International Society for Heart and Lung Transplantation (ISHLT) guidelines. The heart transplant population includes an increasing frequency of patients on mechanical circulatory support (MCS), often with ongoing infection and/or presensitization, who are at high immunological risk but also vulnerable to infectious complications. The number of patients with renal impairment is also growing due to lengthening waiting times, intensifying the need for strategies that minimize calcineurin inhibitor (CNI) toxicity. Additionally, the importance of donor-specific antibodies (DSA) in predicting graft failure is influencing immunosuppressive regimens. In light of these developments, and in view of the lack of evidence-based prescribing criteria, experts from Germany, Austria, and Switzerland convened to identify indications for rATG induction in heart transplantation and to develop an algorithm for its use based on patient characteristics.

Clinical experience of combined HeartWare ventricular assist device and implantable cardioverter defibrillator therapy.

INTRODUCTION: The HeartWare continuous flow ventricular assist device (HVAD) is used in an increasing number of heart failure patients. In those patients, ventricular arrhythmias (VAs) are common and, consequently, many patients already have an implanted implantable cardioverter defibrillator (ICD) in place or receive ICD implantation after left ventricular assist device implantation. However, limited data on feasibility and necessity of combined ICD and HVAD therapy are available. In this study we present our technical and clinical experience. METHODS AND RESULTS: Between 01/2010 and 06/2013, 41 patients received HVAD implantation. Twenty-six HVAD patients who already had an ICD device placed prior to HVAD implantation or received ICD implantation afterwards were enrolled in this study. Peri- and postoperative complications as well as ICD interrogations were documented and analyzed retrospectively. Mean patients age was 58.4 ± 12.6 years; 88.5% of patients were male. During mean follow-up of 12.2 ± 8.9 months, appropriate ICD interventions occurred in 9 patients (34.6%) due to ventricular tachyarrhythmia (n = 7) or ventricular fibrillation (n = 2). An inappropriate ICD intervention was seen in 1 patient (3.9%) due to tachycardic atrial fibrillation. Patients on HVAD with a history of VAs (n = 13) had a significantly higher incidence of ICD interventions compared to patients with primary prophylactic indication for ICD (n = 13; 53.8% vs. 7.7%; P = 0.015). No disturbance of ICD function was seen after HVAD implantation. CONCLUSION: Combined ICD and HVAD therapy was safe and feasible, without electromagnetic interference between ICD and ventricular assist device. The incidence of ICD interventions was high in patients with a history of VAs, but low in patients with ICD implantation for primary prevention.

Efficacy of prophylactic intra-aortic balloon pump therapy in chronic heart failure patients undergoing cardiac surgery.

This study investigated the efficacy of prophylactic intraoperative intra-aortic balloon pump (IABP) usage in chronic heart failure patients with severely reduced left ventricular function undergoing elective cardiac surgery. Between January 2008 and December 2012, 107 patients with severely reduced left ventricular ejection fraction (LVEF <35%) received prophylactic intraoperative IABP implantation during open-heart surgery. Surgical procedures performed were isolated coronary artery bypass grafting (CABG) in 35 patients (32.7%), aortic valve replacement in 12 (11.2%), mitral valve repair or replacement in 15 (14.0%), combined valve and CABG procedures in 27 (25.2%), and other surgical procedures in 18 (16.8%). Results and outcomes were compared with those in a propensity score-matched cohort of 107 patients who underwent cardiac surgery without intraoperative IABP implantation. Matching criteria were age, gender, LVEF, and surgical procedure. Duration of intensive care unit (ICU) stay, duration of hospital stay, and 30-day mortality were markers of outcome. In the IABP group, mean patient age was 69.1 ± 13.7 years; 66.4% (70) were male. All IABPs were placed intraoperatively. Mean duration of IABP application time was 42.4 ± 8.7 h. IABP-related complications occurred in five patients (4.7%), including one case of inguinal bleeding, one case of mesenteric ischemia, and ischemia of the lower limb in three patients. No stroke or major bleeding occurred during IABP support. Mean durations of ICU and hospital stay were 3.38 ± 2.15 days and 7.69 ± 2.02 days, respectively, in the IABP group, and 4.20 ± 3.14 days and 8.57 ± 3.26 days in the control group, showing statistically significant reductions in duration of ICU and hospital stay in the IABP group (ICU stay, P = 0.036; hospital stay, P = 0.015). Thirty-day survival rates were 92.5 and 94.4% in the IABP and control group, respectively, showing no statistically significant difference (P = 0.75). IABP usage in chronic heart failure patients with severely reduced LVEF undergoing cardiac surgery was safe and resulted in shorter ICU and hospital stay but did not influence 7- and 30-day survival rates.

Minimally invasive implantation of biventricular assist devices.

As minimally invasive left ventricular assist device implantation is being advocated and more widely performed, bailout strategies for postoperative right ventricular failure (RVF) become necessary. We describe our surgical technique for additional right ventricular assist device implantation through a third mini-thoracotomy incision. This new technique allows avoidance of sternotomy even if RVF occurs.

Hypoimmune islets achieve insulin independence after allogeneic transplantation in a fully immunocompetent non-human primate.

Allogeneic transplantation of pancreatic islets for patients with difficult-to-control diabetes mellitus is severely hampered by the requirement for continuous immunosuppression and its associated morbidity. We report that allogeneic transplantation of genetically engineered (B2M-/-, CIITA-/-, CD47+), primary, hypoimmune, pseudo-islets (p-islets) results in their engraftment into a fully immunocompetent, diabetic non-human primate wherein they provide stable endocrine function and enable insulin independence without inducing any detectable immune response in the absence of immunosuppression. Hypoimmune primary p-islets may provide a curative cell therapy for type 1 diabetes mellitus.

Four decades of progress in heart-lung transplantation: Two hundred seventy-one cases at a single institution.

OBJECTIVE: The objective of this study is to evaluate survival for combined heart-lung transplant (HLTx) recipients across 4 decades at a single institution. We aim to summarize our contemporary practice based on more than 271 HLTx procedures over 40 years. METHODS: Data were collected from a departmental database and the United Network for Organ Sharing. Recipients younger than age 18 years, those undergoing redo HLTx, or triple-organ system transplantation were excluded, leaving 271 patients for analysis. The pioneering era was defined by date of transplant between 1981 and 2000 (n = 155), and the modern era between 2001 and 2022 (n = 116). Survival analysis was performed using cardinality matching of populations based on donor and recipient age, donor and recipient sex, ischemic time, and sex matching. RESULTS: Between 1981 and 2022, 271 HLTx were performed at a single institution. Recipients in the modern era were older (age 42 vs 34 y; P < .001) and had shorter waitlist times (78 vs 234 days; P < .001). Allografts from female donors were more common in the modern era (59% vs 39%; P = .002). In the matched survival analysis, 30-day survival (97% vs 84%; P = .005), 1-year survival (89% vs 77%; P = .041), and 10-year survival (53% vs 26%; P = .012) significantly improved in the modern era relative to the pioneering era, respectively. CONCLUSIONS: Long-term survival in HLTx is achievable with institutional experience and may continue to improve in the coming decades. Advances in mechanical circulatory support, improved maintenance immunosuppression, and early recognition and management of acute complications such as primary graft dysfunction and acute rejection have dramatically improved the prognosis for recipients of HLTx in our contemporary institutional experience.

Hypoimmune induced pluripotent stem cells survive long term in fully immunocompetent, allogeneic rhesus macaques.

Genetic engineering of allogeneic cell therapeutics that fully prevents rejection by a recipient's immune system would abolish the requirement for immunosuppressive drugs or encapsulation and support large-scale manufacturing of off-the-shelf cell products. Previously, we generated mouse and human hypoimmune pluripotent (HIP) stem cells by depleting HLA class I and II molecules and overexpressing CD47 (B2M-/-CIITA-/-CD47+). To determine whether this strategy is successful in non-human primates, we engineered rhesus macaque HIP cells and transplanted them intramuscularly into four allogeneic rhesus macaques. The HIP cells survived unrestricted for 16 weeks in fully immunocompetent allogeneic recipients and differentiated into several lineages, whereas allogeneic wild-type cells were vigorously rejected. We also differentiated human HIP cells into endocrinologically active pancreatic islet cells and showed that they survived in immunocompetent, allogeneic diabetic humanized mice for 4 weeks and ameliorated diabetes. HIP-edited primary rhesus macaque islets survived for 40 weeks in an allogeneic rhesus macaque recipient without immunosuppression, whereas unedited islets were quickly rejected.

Immunobiology of naïve and genetically modified HLA-class-I-knockdown human embryonic stem cells.

Human embryonic stem cells (hESCs) can serve as a universal cell source for emerging cell or tissue replacement strategies, but immune rejection of hESC derivatives remains an unsolved problem. Here, we sought to describe the mechanisms of rejection for naïve hESCs and upon HLA class I (HLA I) knockdown (hESC(KD)). hESCs were HLA I-positive but negative for HLA II and co-stimulatory molecules. Transplantation of naïve hESC into immunocompetent Balb/c mice induced substantial T helper cell 1 and 2 (Th1 and Th2) responses with rapid cell death, but hESCs survived in immunodeficient SCID-beige recipients. Histology revealed mainly macrophages and T cells, but only scattered natural killer (NK) cells. A surge of hESC-specific antibodies against hESC class I, but not class II antigens, was observed. Using HLA I RNA interference and intrabody technology, HLA I surface expression of hESC(KD) was 88%-99% reduced. T cell activation after hESC(KD) transplantation into Balb/c was significantly diminished, antibody production was substantially alleviated, the levels of graft-infiltrating immune cells were reduced and the survival of hESC(KD) was prolonged. Because of their very low expression of stimulatory NK ligands, NK-susceptibility of naïve hESCs and hESC(KD) was negligible. Thus, HLA I recognition by T cells seems to be the primary mechanism of hESC recognition, and T cells, macrophages and hESC-specific antibodies participate in hESC killing.

Late profound muscle weakness following heart transplantation due to Danon disease.

INTRODUCTION: Postoperative muscle weakness is a serious complication in surgical intensive care patients. It is mostly described as critical illness polyneuromyopathy. Risk factors include intensive care length of stay, sepsis, poor glycemic control, and combined use of corticosteroids and neuromuscular blocking agents, malnutrition, and electrolyte imbalance. METHODS: We report a case of late-progressive, profound weakness after heart transplantation for noncompaction cardiomyopathy which required prolonged mechanical ventilation. The patient's muscle strength recovered completely after prolonged rehabilitation. RESULTS: Electromyographic assessment showed myopathy. Muscle biopsy revealed Danon disease, a genetic disorder affecting the lysosomal-associated membrane protein 2 gene (LAMP2). CONCLUSIONS: The finding of this genetic disorder was unexpected, because the preoperative echocardiographic diagnosis of noncompaction cardiomyopathy has not been reported in Danon disease. This report underlines the need for early availability of pathology results from the explanted heart, which showed the same disorder.