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Autologous induced pluripotent stem cells (iPSCs) constitute an unlimited cell source for patient-specific cell-based organ repair strategies. However, their generation and subsequent differentiation into specific cells or tissues entail cell line-specific manufacturing challenges and form a lengthy process that precludes acute treatment modalities. These shortcomings could be overcome by using prefabricated allogeneic cell or tissue products, but the vigorous immune response against histo-incompatible cells has prevented the successful implementation of this approach. Here we show that both mouse and human iPSCs lose their immunogenicity when major histocompatibility complex (MHC) class I and II genes are inactivated and CD47 is over-expressed. These hypoimmunogenic iPSCs retain their pluripotent stem cell potential and differentiation capacity. Endothelial cells, smooth muscle cells, and cardiomyocytes derived from hypoimmunogenic mouse or human iPSCs reliably evade immune rejection in fully MHC-mismatched allogeneic recipients and survive long-term without the use of immunosuppression. These findings suggest that hypoimmunogenic cell grafts can be engineered for universal transplantation.Genetic engineering prevents immune rejection of allogeneic cell transplants derived from iPSCs.

An enhanced recovery after surgery (ERAS) protocol is a multimodal and multi-professional strategy aiming to accelerate postoperative convalescence. Pre-, intra- and postoperative measures might furthermore reduce postoperative complications and hospital length of stay (LOS) in a cost-effective way. We hypothesized that our unique ERAS protocol leads to shorter stays on the intensive care unit (ICU) and a quicker discharge without compromising patient safety. This retrospective single center cohort study compares data of n = 101 patients undergoing minimally invasive heart valve surgery receiving a comprehensive ERAS protocol and n = 111 patients receiving routine care. Hierarchically ordered primary endpoints are postoperative hospital length of stay (LOS), postoperative complications and ICU LOS. Patients risk profiles and disease characteristics were comparably similar. Age was relevantly different between the groups (56 (17) vs. 57.5 (13) years, p = 0.015) and therefore adjusted. Postoperative LOS was significantly lower in ERAS group (6 (2) days vs. 7 (1) days, p<0.01). No significant differences, neither in intra- or postoperative complications, nor in the number of readmissions (15.8% vs. 9.9%, p = 0.196) were shown. In hospital LOS (7 (3) days vs. 8 (4) days, p<0.01) and ICU LOS (18.5 (6) hours vs. 26.5 (29) hours, p<0.01) a considerable difference was shown. The ERAS protocol for minimally invasive heart valve surgery is safe and feasible in an elective setting and leads to a quicker hospital discharge without compromising patient safety. However, further investigation in a randomized setting is needed.

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are a promising tool for drug testing and modelling genetic disorders. Abnormally low upstroke velocity is a current limitation. Here we investigated the use of 3D engineered heart tissue (EHT) as a culture method with greater resemblance to human heart tissue in comparison to standard technique of 2D monolayer (ML) format. I Na was measured in ML or EHT using the standard patch-clamp technique. I Na density was ~1.8 fold larger in EHT (−18.5 ± 1.9 pA/pF; n = 17) than in ML (−10.3 ± 1.2 pA/pF; n = 23; p < 0.001), approaching densities reported for human CM. Inactivation kinetics, voltage dependency of steady-state inactivation and activation of I Na did not differ between EHT and ML and were similar to previously reported values for human CM. Action potential recordings with sharp microelectrodes showed similar upstroke velocities in EHT (219 ± 15 V/s, n = 13) and human left ventricle tissue (LV, 253 ± 7 V/s, n = 25). EHT showed a greater resemblance to LV in CM morphology and subcellular Na V 1.5 distribution. I Na in hiPSC-CM showed similar biophysical properties as in human CM. The EHT format promotes I Na density and action potential upstroke velocity of hiPSC-CM towards adult values, indicating its usefulness as a model for excitability of human cardiac tissue.

A short-term increase in ventricular filling leads to an immediate (Frank-Starling mechanism) and a slower (Anrep effect) rise in cardiac contractility, while long-term increased cardiac load (e.g., in arterial hypertension) decreases contractility. Whether these answers to mechanical tension are mediated by specific sensors in cardiomyocytes remains elusive. In this study, the piezo2 protein was evaluated as a potential mechanosensor. Piezo2 was found to be upregulated in various rat and mouse cardiac tissues upon mechanical or pharmacological stress. To investigate its function, C57BL/6J mice with homozygous cardiomyocyte-specific piezo2 knockout [Piezo2-KO] were created. To this end, α-MHC-Cre mice were crossed with homozygous “floxed” piezo2 mice. α-MHC-Cre mice crossed with wildtype mice served as controls [WT-Cre + ]. In cardiomyocytes of Piezo2-KO mice, piezo2 mRNA was reduced by > 90% and piezo2 protein was not detectable. Piezo2-KO mice displayed no morphological abnormalities or altered cardiac function under nonstressed conditions. In a subsequent step, hearts of Piezo2-KO or WT-Cre + -mice were stressed by either three weeks of increased afterload (angiotensin II, 2.5 mg/kg/day) or one week of hypercontractility (isoprenaline, 30 mg/kg/day). As expected, angiotensin II treatment in WT-Cre + -mice resulted in higher heart and lung weight (per body weight, + 38%, + 42%), lower ejection fraction and cardiac output (− 30%, − 39%) and higher left ventricular anterior and posterior wall thickness (+ 34%, + 37%), while isoprenaline led to higher heart weight (per body weight, + 25%) and higher heart rate and cardiac output (+ 24%, + 54%). The Piezo2-KO mice reacted similarly with the exception that the angiotensin II-induced increases in wall thickness were blunted and the isoprenaline-induced increase in cardiac output was slightly less pronounced. As cardiac function was neither severely affected under basal nor under stressed conditions in Piezo2-KO mice, we conclude that piezo2 is not an indispensable mechanosensor in cardiomyocytes.

Background ERAS (Enhanced Recovery After Surgery) is a multidisciplinary and integrative approach with the goal of optimizing the postoperative recovery. We aimed to analyze the economic impact of a newly established ERAS protocol in minimally invasive heart valve surgery at our institution. Methods ERAS protocol was implemented in 61 consecutive patients who were referred for elective minimally-invasive aortic or mitral valve surgery, between February 1, 2018 and March 31, 2019 ( ERAS-group ). Another 69 patients who underwent elective minimally-invasive heart valve surgery during the same time period were managed according to the hospital standards ( Control-group ). A detailed cost comparison analysis was carried out from a hospital perspective using a micro-costing approach. Results The total in-hospital stay was significantly shorter in the ERAS-group compared to the Control-group (6.1 ± 2.6 vs 7.7 ± 3.8 days; p  = 0.008) resulting in significant cost savings of €1087.2 per patient ( p  = 0.003). Due to the intensified physiotherapy in the ERAS protocol, the costs for physiotherapy were €94.3 higher compared to the Control-group ( p  < 0.001). The total costs in the ERAS cohort were €11,200.0 ± 3029.6/patient compared to € 13,109.8 ± 4527.5/patient in the Control-Group resulting in cost savings of €1909.8 patient due to the implementation of the ERAS protocol ( p  = 0.006). Conclusion Implementation of an ERAS-protocol in minimally-invasive cardiac surgery can be carried out safely with a fast postoperative recovery of the patient. ERAS results in a financial benefit of up to €1909 per patient and therefore will play a key role in modern cardiac surgery in the near future.

The utility of autologous induced pluripotent stem cell (iPSC) therapies for tissue regeneration depends on reliable production of immunologically silent functional iPSC derivatives. However, rejection of autologous iPSC-derived cells has been reported, although the mechanism underlying rejection is largely unknown. We hypothesized that de novo mutations in mitochondrial DNA (mtDNA), which has far less reliable repair mechanisms than chromosomal DNA, might produce neoantigens capable of eliciting immune recognition and rejection. Here we present evidence in mice and humans that nonsynonymous mtDNA mutations can arise and become enriched during reprogramming to the iPSC stage, long-term culture and differentiation into target cells. These mtDNA mutations encode neoantigens that provoke an immune response that is highly specific and dependent on the host major histocompatibility complex genotype. Our results reveal that autologous iPSCs and their derivatives are not inherently immunologically inert for autologous transplantation and suggest that iPSC-derived products should be screened for mtDNA mutations.

Protocols for \"Enhanced recovery after surgery (ERAS)\" are on the rise in different surgical disciplines and represent one of the most important recent advancements in perioperative medical care. In cardiac surgery, only few ERAS protocols have been described in the past. At University Heart Center Hamburg, Germany, we invented an ERAS protocol for patients undergoing minimally invasive cardiac valve surgery. In this retrospective single center study, we aimed to describe the implementation of our ERAS program and to evaluate the results of the first 50 consecutive patients. Our ERAS protocol was developed according to a modified Kern cycle by an expert group, literature search, protocol creation and pilot implementation in the clinical practice. Data of the first 50 consecutive patients undergoing minimally invasive cardiac valve surgery were analysed retrospectively. The key features of our multidisciplinary ERAS protocol are physiotherapeutic prehabilitation, minimally invasive valve surgery techniques, modified cardiopulmonary bypass management, fast-track anaesthesia with on- table extubation and early mobilisation. A total of 50 consecutive patients (mean age of 51.9±11.9 years, mean STS score of 0.6±0.3) underwent minimally-invasive mitral or aortic valve surgery. The adherence to the ERAS protocol was high and neither protocol related complications nor in-hospital mortality occurred. 12% of the patients developed postoperative atrial fibrillation, postoperative delirium emerged in two patients and reintubation was required in one patient. Intensive care unit stay was 14.0±7.4 hours and total hospital stay 6.2±2.9 days. Our ERAS protocol is feasible and safe in minimally-invasive cardiac surgery setting and has a clear potential to improve patients outcome.

Background Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly used in patients with critical cardiopulmonary failure. To investigate the association between hospital VA-ECMO procedure volume and outcomes in a large, nationwide registry. Methods By using administrative data from the German Federal Health Monitoring System, we analyzed all VA-ECMO procedures performed in Germany from 2013 to 2016 regarding the association of procedural volumes with outcomes and complications. Results During the study period, 10,207 VA-ECMO procedures were performed; mean age was 61 years, 43.4% had prior CPR, and 71.2% were male patients. Acute coronary syndrome was the primary diagnosis for VA-ECMO implantation ( n  = 6202, 60.8%). The majority of implantations ( n  = 5421) were performed at hospitals in the lowest volume category (≤ 50 implantations per year). There was a significant association between annualized volume of VA-ECMO procedures and 30-day in-hospital mortality for centers with lower vs. higher volume per year. Multivariable logistic regression showed an increased 30-day in-hospital mortality at hospitals with the lowest volume category (adjusted odds ratio 1.13, 95% confidence interval [CI] 1.01–1.27, p  = 0.034). Similarly, higher likelihood for complications was observed at hospitals with lower vs. higher annual VA-ECMO volume (adjusted odds ratio 1.46, 95% CI 1.29–1.66, p  = 0.001). Conclusions In this analysis of more than 10,000 VA-ECMO procedures for cardiogenic shock, the majority of implantations were performed at hospitals with the lowest annual volume. Thirty-day in-hospital mortality and likelihood for complications were higher at hospitals with the lowest annual VA-ECMO volume.

MASS phenotype is a connective tissue disorder clinically overlapping with Marfan syndrome and caused by pathogenic variants in FBN1 . We report four patients from three families presenting with a MASS-like phenotype consisting of tall stature, arachnodactyly, spinal deformations, dural ectasia, pectus and/or feet deformations, osteoarthritis, and/or high arched palate. Gene panel sequencing was negative for FBN1 variants. However, it revealed likely pathogenic missense variants in three individuals [c.3936G > T p.(Lys1312Asn), c.193G > A p.(Asp65Asn)] and a missense variant of unknown significance in the fourth patient [c.4013G > A p.(Ser1338Asn)] in propeptide coding regions of COL2A1 . Pathogenic COL2A1 variants are associated with type II collagenopathies comprising a remarkable clinical variablility. Main features include skeletal dysplasia, ocular anomalies, and auditory defects. A MASS-like phenotype has not been associated with COL2A1 variants before. Thus, the identification of likely pathogenic COL2A1 variants in our patients expands the phenotypic spectrum of type II collagenopathies and suggests that a MASS-like phenotype can be assigned to various hereditary disorders of connective tissue. We compare the phenotypes of our patients with related disorders of connective tissue and discuss possible pathomechanisms and genotype–phenotype correlations for the identified COL2A1 variants. Our data recommend COL2A1 sequencing in FBN1 -negative patients suggestive for MASS/Marfan-like phenotype (without aortopathy).

Persistent inflammation is a hallmark of many human diseases, including anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) and atherosclerosis. Here, we describe a dominant trigger of inflammation: human serum factor H-related protein FHR1. In vitro, this protein selectively binds to necrotic cells via its N-terminus; in addition, it binds near necrotic glomerular sites of AAV patients and necrotic areas in atherosclerotic plaques. FHR1, but not factor H, FHR2 or FHR3 strongly induces inflammasome NLRP3 in blood-derived human monocytes, which subsequently secrete IL-1β, TNFα, IL-18 and IL-6. FHR1 triggers the phospholipase C-pathway via the G-protein coupled receptor EMR2 independent of complement. Moreover, FHR1 concentrations of AAV patients negatively correlate with glomerular filtration rates and associate with the levels of inflammation and progressive disease. These data highlight an unexpected role for FHR1 during sterile inflammation, may explain why FHR1-deficiency protects against certain diseases, and identifies potential targets for treatment of auto-inflammatory diseases. FHR1 is a serum protein implicated in complement regulation. Here the authors show that human FHR1 binds to necrotic cells, triggering inflammasome activation in monocytes in culture, localizes to necrotic tissue and correlates with inflammatory cytokine levels in vasculopathies.