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Background Postural tachycardia syndrome (POTS) is characterized by orthostatic intolerance and heart rate increase in an upright position without orthostatic hypotension. It has been described after coronavirus disease-19 (COVID-19) as well as after COVID-19 vaccination. Case summary A 54-year-old female patient presented with a 9-months history of severe orthostatic intolerance since COVID-19 vaccination with messenger RNA (mRNA)-1273 (Spikevax, Moderna). Except for diet-controlled coeliac disease, the patient was healthy, had no allergies, and did not take regular medication. Tilt table testing revealed a significant heart rate increase to 168 bpm without orthostatic hypotension accompanied by light-headedness, nausea, and syncope, findings consistent with POTS. Potential underlying causes including anaemia, thyroid dysfunction, adrenal insufficiency, pheochromocytoma, (auto)-immune disease, chronic inflammation as well as neurological causes were ruled out. Echocardiography and cardiac stress magnetic resonance imaging (MRI) did not detect structural or functional heart disease or myocardial ischaemia. Forty-eight-hour-electrocardiogram (ECG) showed no tachycardias other than sinus tachycardia. Finally, genomic analysis did not detect an inherited arrhythmia syndrome. Serologic analysis revealed adequate immune response to mRNA-1273 vaccination without signs of previous severe acute respiratory syndrome-coronavirus-2 infection. While ivabradine was not tolerated and metoprolol extended release only slightly improved symptoms, physical exercise reduced orthostatic intolerance moderately. At a 5-months follow-up, the patient remained dependant on assistance for activities of daily living. Discussion The temporal association of POTS with the COVID-19 vaccination in a previously healthy patient and the lack of evidence of an alternative aetiology suggests COVID-19 vaccination is the potential cause of POTS in this patient. To our knowledge, this is the first case reporting severe, long-term, and treatment-refractory POTS following COVID-19 vaccination with mRNA1273. [ABSTRACT FROM AUTHOR]

(1) Background: Ongoing symptoms after mild or moderate acute coronavirus disease 19 (COVID-19) substantially affect health-related quality of life (HRQoL). However, follow-up data on HRQoL are scarce. We characterized the change in HRQoL over time in post-COVID-19 patients who initially suffered from mild or moderate acute COVID-19 without hospitalization. (2) Methods: Outpatients who visited an interdisciplinary post-COVID-19 consultation at the University Hospital Zurich and suffered from ongoing symptoms after acute COVID-19 were included in this observational study. HRQoL was assessed using established questionnaires. Six months after baseline, the same questionnaires and a self-constructed questionnaire about the COVID-19 vaccination were distributed. (3) Results: In total, 69 patients completed the follow-up, of whom 55 (80%) were female. The mean (SD) age was 44 (12) years and the median (IQR) time from symptom onset to completing the follow-up was 326 (300, 391) days. The majority of patients significantly improved in EQ-5D-5L health dimensions of mobility, usual activities, pain and anxiety. Furthermore, according to the SF-36, patients showed clinically relevant improvements in physical health, whereas no significant change was found regarding mental health. (4) Conclusions: Physical aspects of HRQoL in post-COVID-19 patients relevantly improved over 6 months. Future studies are needed to focus on potential predictors that allow for establishing individual care and early interventions. [ABSTRACT FROM AUTHOR]

(1) Background: Lung tissue involvement is frequently observed in acute COVID-19. However, it is unclear whether CT findings at follow-up are associated with persisting respiratory symptoms after initial mild or moderate infection. (2) Methods: Chest CTs of patients with persisting respiratory symptoms referred to the post-COVID-19 outpatient clinic were reassessed for parenchymal changes, and their potential association was evaluated. (3) Results: A total of 53 patients (31 female) with a mean (SD) age of 46 (13) years were included, of whom 89% had mild COVID-19. Median (quartiles) time from infection to CT was 139 (86, 189) days. Respiratory symptoms were dyspnea (79%), cough (42%), and thoracic pain (64%). Furthermore, 30 of 53 CTs showed very discrete and two CTs showed medium parenchymal abnormalities. No severe findings were observed. Mosaic attenuation (40%), ground glass opacity (2%), and fibrotic-like changes (25%) were recorded. No evidence for an association between persisting respiratory symptoms and chest CT findings was found. (4) Conclusions: More than half of the patients with initially mild or moderate infection showed findings on chest CT at follow-up. Respiratory symptoms, however, were not related to any chest CT finding. We, therefore, do not suggest routine chest CT follow-up in this patient group if no other indications are given. [ABSTRACT FROM AUTHOR]

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Copyright of Praxis (16618157) is the property of Aerzteverlag medinfo AG and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

There seems to be an uncertainty about the periprocedural management of direct oral anticoagulants, which might be due to the different pharmacological and pharmacokinetic properties of the currently existing substances Apixaban, Dabigatran, Edoxaban and Rivaroxaban.Thus, using DOAC requires the calculation and evaluation of the individual riskfor bleeding and thromboembolism. Monitoring of the therapy is not common, but in some situations the concentration of the substance might be interesting. Depending on the substance different methods for monitoring exist. It is important to be aware of possible falsification of other coagulation markers. In case of severe bleeding PPSB will be necessary. So far Praxbind® (Idaru zumab) is the only available antidote. Flowever, as a result of current research, further therapy options concerning reversal for factor Xa inhibitors might be available in the near future. [ABSTRACT FROM AUTHOR]

The pathogenesis of atherosclerosis involves dysfunctions of vascular endothelial cells and smooth muscle cells as well as blood borne inflammatory cells such as monocyte-derived macrophages. In vitro experiments towards a better understanding of these dysfunctions are typically performed in two-dimensional cell culture systems. However, these models lack both the three-dimensional structure and the physiological pulsatile flow conditions of native arteries. We here describe the development and initial characterization of a tissue engineered artery equivalent, which is composed of human primary endothelial and smooth muscle cells and is exposed to flow in vitro. Histological analyses showed formation of a dense tissue composed of a tight monolayer of endothelial cells supported by a basement membrane and multiple smooth muscle cell layers. Both low (LDL) and high density lipoproteins (HDL) perfused through the artery equivalent were recovered both within endothelial cells and in the sub-endothelial intima. After activation of the endothelium with either tumour necrosis factor alpha (TNFα) or LDL, monocytes circulated through the model were found to adhere to the activated endothelium and to transmigrate into the intima. In conclusion, the described tissue engineered human artery equivalent model represents a significant step towards a relevant in vitro platform for the systematic assessment of pathogenic processes in atherosclerosis independently of any systemic factors. [ABSTRACT FROM AUTHOR]

Due to impressive improvements in surgical repair options, even patients with complex congenital heart disease (CHD) may survive into adulthood and have a high risk of end-stage heart failure. Thus, the number of patients with CHD needing heart transplantation (HTx) has been increasing in the last decades. This paper summarizes the changing etiology of causes of death in heart failure in CHD. The main reasons, contraindications, and risks of heart transplantation in CHD are discussed and underlined with three case vignettes. Compared to HTx in acquired heart disease, HTx in CHD has an increased risk of perioperative death and rejection. However, outcome of HTx for complex CHD has improved over the past 20 years. Additionally, mechanical support options might decrease the waiting list mortality in the future. The number of patients needing heart-lung transplantation (especially for Eisenmenger's syndrome) has decreased in the last years. Lung transplantation with intracardiac repair of a cardiac defect is another possibility especially for patients with interatrial shunts. Overall, HTx will remain an important treatment option for CHD in the near future. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to demonstrate the feasibility of combining the novel heart valve replacement technologies of: 1) tissue engineering; and 2) minimally-invasive implantation based on autologous cells and composite self-expandable biodegradable biomaterials. Background: Minimally-invasive valve replacement procedures are rapidly evolving as alternative treatment option for patients with valvular heart disease. However, currently used valve substitutes are bioprosthetic and as such have limited durability. To overcome this limitation, tissue engineering technologies provide living autologous valve replacements with regeneration and growth potential. Methods: Trileaflet heart valves fabricated from biodegradable synthetic scaffolds, integrated in self-expanding stents and seeded with autologous vascular or stem cells (bone marrow and peripheral blood), were generated in vitro using dynamic bioreactors. Subsequently, the tissue engineered heart valves (TEHV) were minimally-invasively implanted as pulmonary valve replacements in sheep. In vivo functionality was assessed by echocardiography and angiography up to 8 weeks. The tissue composition of explanted TEHV and corresponding control valves was analyzed. Results: The transapical implantations were successful in all animals. The TEHV demonstrated in vivo functionality with mobile but thickened leaflets. Histology revealed layered neotissues with endothelialized surfaces. Quantitative extracellular matrix analysis at 8 weeks showed higher values for deoxyribonucleic acid, collagen, and glycosaminoglycans compared to native valves. Mechanical profiles demonstrated sufficient tissue strength, but less pliability independent of the cell source. Conclusions: This study demonstrates the principal feasibility of merging tissue engineering and minimally-invasive valve replacement technologies. Using adult stem cells is successful, enabling minimally-invasive cell harvest. Thus, this new technology may enable a valid alternative to current bioprosthetic devices. [Copyright &y& Elsevier]

Abstract: Objective: A major shortcoming in contemporary congenital heart surgery is the lack of viable replacement materials with the capacity of growth and regeneration. Here we focused on living autologous patches engineered from human umbilical cord derived fibroblasts and endothelial progenitor cells (EPCs) as a ready-to-use cell source for paediatric cardiovascular tissue engineering. Methods: EPCs were isolated from 20ml fresh umbilical cord blood by density gradient centrifugation and myofibroblasts were harvested from umbilical cord tissue. Cells were differentiated and expanded in vitro using nutrient media containing growth factors. Before seeding, cell-phenotypes were assessed by immuno-histochemistry. Biodegradable patches fabricated from synthetic polymers (PGA/P4HB) were seeded with myofibroblasts followed by endothelialization with EPCs. All patches were cultured in a perfusion bioreactor. A subgroup of patches was additionally stimulated by cyclic strain. Analysis of the neo-tissues comprised histology, immuno-histochemistry, extracellular matrix (ECM) analysis and biomechanical testing. Results: Endothelial phenotypes of EPCs before seeding were confirmed by Ac-Dil-LDL, CD 31, von-Willebrand-Factor and eNOS staining. Histology of the seeded patches demonstrated layered viable tissue formation in all samples. The cells in the newly formed tissues expressed myofibroblast markers, such as desmin and alpha-SMA. The EPCs derived neo-endothelia showed constant endothelial phenotypes (CD 31, vWF). major constituents of ECM such as collagen and proteoglycans were biochemically detected. Stress–strain properties of the patches showed features of native-analogous tissues. Conclusions: Living tissue engineered patches can be successfully generated from human umbilical cord derived myofibroblasts and EPCs. This new cell source may enable the tissue engineering of versatile, living, autologous replacement materials for congenital cardiac interventions. [Copyright &y& Elsevier]

Objectives: Ischemia/reperfusion injury is characterized by endothelial cell activation leading to increased expression of adhesion molecules such as inter-cellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, endothelial- and platelet-selectin (E- and P-selectin), and to the subsequent recruitment of leukocytes. The aim of the present study was to investigate the respective effects of a proinflammatory cytokine (tumor necrosis factor alpha , TNF-α), hypoxia and/or reoxygenation on adhesion molecule expression and natural killer (NK) cell adhesion in an in vitro model of I/R. Methods: Human aortic endothelial cells (HAEC) were stimulated in vitro for 8h with TNF-α (1000 U/ml) and exposed to hypoxia (1% O2), reoxygenation (21% O2) or different combinations thereof. Cell surface expression of ICAM-1, VCAM-1 and E-/P-selectin on HAEC was analyzed by flow cytometry, and culture supernatants were tested for soluble adhesion molecules by ELISA. Rolling adhesion of NK cells on HAEC was determined using a rotating assay. Results: Untreated HAEC constitutively expressed ICAM-1 on their surface but neither expressed E-/P-selectin, VCAM-1, nor shedded soluble adhesion molecules. Exposure of HAEC to hypoxia or hypoxia and reoxygenation did not upregulate cell surface expression or shedding of adhesion molecules. In contrast, TNF-α significantly upregulated cell surface expression of ICAM-1, VCAM-1, and E-/P-selectin and led to the shedding of ICAM-1 and E-selectin. Combined treatment of HAEC with TNF-α, hypoxia and reoxygenation reduced E-/P-selectin surface expression and enhanced E-selectin shedding, but did not further influence ICAM-1 and VCAM-1. Soluble VCAM-1 was not detected. NK cell adhesion on HAEC increased 4-fold after TNF-α stimulation, but was not affected by hypoxia or hypoxia and reoxygenation. Conclusions: Both the expression of endothelial adhesion molecules and rolling NK cell adhesion was upregulated by TNF-α but not by hypoxia alone or hypoxia followed by reoxygenation supporting the view that anti-inflammatory treatment may reduce ischemia/reperfusion injury. [Copyright &y& Elsevier]

Background: Cardiac sarcoidosis (CS) is a chronic inflammatory disease characterised by non-caseating granulomas, while arrhythmogenic cardiomyopathy (ACM) is a genetic condition mainly affecting desmosomal proteins. The coexistence of CS and genetic variants associated with ACM is not well understood, creating challenges in diagnosis and management. This study aimed to describe the clinical, imaging and genetic features of patients with both conditions., Methods: This was a multicentre retrospective case-control study involving three groups of patients: those with biopsy-proven CS and pathogenic or likely pathogenic genetic variants linked to ACM (n=5); patients with genetic variants but no CS (n=5); and patients with CS without genetic variants (n=5). Clinical data, including symptoms, electrocardiographic findings and imaging results from echocardiography, cardiac magnetic resonance and positron-emission tomography, were analysed., Results: Patients with CS and genetic variants were more likely to exhibit atrioventricular block (100%), PR prolongation (204 ms vs 160 ms) and paroxysmal atrial fibrillation (80%) compared with those with genetic variants alone (0% for both). Imaging findings showed a higher prevalence of septal involvement in patients with both conditions (80%) than in those with genetic variants alone (20%). No significant differences were observed between patients with CS and genetic variants and those with CS without genetic variants. The genetic variants identified included variants in PKP2 (40%), DSG2 (20%), DSP (20%) and TTN (20%)., Conclusions: The coexistence of CS and ACM-associated genetic variants is associated with distinct clinical features, including PR prolongation, AVB1°, septal involvement and paroxysmal atrial fibrillation. These findings emphasise the need to evaluate for CS in individuals with ACM and associated genetic variants who present with conduction abnormalities or septal involvement, guiding tailored diagnostic and therapeutic strategies., Competing Interests: Competing interests: AMS has received speaker/consulting fees from Bayer Healthcare, Biotronik, Medtronic, Pfizer, Stride Bio Inc. and Zoll. AJF declares fees from Abbott, Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Novartis, Pierre Fabre, Pfizer, Roche, Vifor and Zoll, as well as grant support by Novartis, AstraZeneca and Berlin Heart unrelated to this article. AG is supported by research funding grants from the Promedica Foundation and Max and Sophielene Iten-Kohaut Foundation. VAR is supported by research funding grants from the Rutishauser Foundation. EA received a grant from the Italian Ministry of Health (GR-2019-12368506; principal investigator of the investigator-driven MYTHS (Myocarditis Therapy with Steroids) trial) and a grant from Italian Ministry of Health and NextGenerationEU (PNRR-MAD-2022-12376225), serves as consultant for Lexeo and served as consultant for Kiniksa, AstraZeneca and Cytokinetics. All other authors declare no conflict of interest related to this manuscript., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Object: Cerebral cavernous malformations (CCMs) are among the most prevalent cerebrovascular malformations, and endothelial cells seem to play a major role in the disease. However, the underlying mechanisms, including endothelial intercellular communication, have not yet been fully elucidated. In this article, the authors focus on the endothelial junction proteins CD31, VE-cadherin, and occludin as important factors for functional cell-cell contacts known as vascular adhesion molecules and adherence and tight junctions., Methods: Thirteen human CCM specimens and 6 control tissue specimens were cryopreserved and examined for the presence of VE-cadherin, occludin, and CD31 by immunofluorescence staining. Protein quantification was performed by triplicate measurements using western blot analysis., Results: Immunofluorescent analyses of the CCM sections revealed a discontinuous pattern of dilated microvessels and capillaries as well as increased expression of occludin, VE-cadherin, and CD31 in the intima and in the enclosed parenchymal tissue compared with controls. Protein quantification confirmed these findings by showing upregulation of the levels of these proteins up to 2-6 times., Conclusions: A protocol enabling the molecular and morphological examination of the intercellular contact proteins in human CCM was validated. The abnormal and discontinuous pattern in these endothelial cell-contact proteins compared with control tissue explains the loose intercellular junctions that are considered to be one of the causes of CCM-associated bleeding or transendothelial oozing of erythrocytes. Despite the small number of specimens, this study demonstrates for the first time a quantitative analysis of endothelial junction proteins in human CCM.

Background and Aim of the Study: Fetal stem cells represent a promising cell source for heart valve tissue engineering. In particular, amniotic fluid-derived cells (AFDC) have been shown to lead to autologous fetal-like heart valve tissues in vitro for pediatric application. In order to expand the versatility of these cells also for adult application, cryopreserved AFDC were investigated as a potential life-long available cell source for heart valve tissue engineering., Methods: Human AFDC were isolated using CD133 magnetic beads, and then differentiated and analyzed. After expansion of CD133- as well as CD133+ cells up to passage 7, a part of the cells was cryopreserved. After four months, the cells were re-cultured and phenotyped by flow cytometry and immunohistochemistry, including expression of CD44, CD105, CD90, CD34, CD31, CD141, eNOS and vWF, and compared to their non-cryopreserved counterparts. The stem cell potential was investigated in differentiation assays. The viability of cryopreserved AFDC for heart valve tissue engineering was assessed by creating heart valve leaflets in vitro., Results: After cryopreservation, amniotic fluid-derived CD133- and CD133+ cells retained their stem cell-like phenotype, expressing mainly CD44, CD90 and CD105. This staining pattern was comparable to that of their non-cryopreserved counterparts. Moreover, CD133- cells demonstrated differentiation potential into osteoblast-like and adipocyte-like cells. CD133+ cells showed characteristics of endothelial-like cells by eNOS, CD141 and beginning vWF expression. When used for the fabrication of heart valve leaflets, cryopreserved CD133- cells produced extracellular matrix elements comparable to their non-cryopreserved counterparts. Moreover, the resulting tissues showed a cellular layered tissue formation covered by functional endothelia. The mechanical properties were similar to those of tissues fabricated from non-cryopreserved cells., Conclusion: The study results suggest that the use of cell bank technology fetal amniotic fluid-derived stem cells might represent a life-long available autologous cell source for heart valve tissue engineering, and also for adult application.

Background: A novel concept providing prenatally tissue engineered human autologous heart valves based on routinely obtained fetal amniotic fluid progenitors as single cell source is introduced., Methods and Results: Fetal human amniotic progenitors were isolated from routinely sampled amniotic fluid and sorted using CD133 magnetic beads. After expansion and differentiation, cell phenotypes of CD133- and CD133+ cells were analyzed by immunohistochemistry and flowcytometry. After characterization, CD133- derived cells were seeded onto heart valve leaflet scaffolds (n=18) fabricated from rapidly biodegradable polymers, conditioned in a pulse duplicator system, and subsequently coated with CD133+ derived cells. After in vitro maturation, opening and closing behavior of leaflets was investigated. Neo-tissues were analyzed by histology, immunohistochemistry, and scanning electron microscopy (SEM). Extracellular matrix (ECM) elements and cell numbers were quantified biochemically. Mechanical properties were assessed by tensile testing. CD133- derived cells demonstrated characteristics of mesenchymal progenitors expressing CD44 and CD105. Differentiated CD133+ cells showed features of functional endothelial cells by eNOS and CD141 expression. Engineered heart valve leaflets demonstrated endothelialized tissue formation with production of ECM elements (GAG 80%, HYP 5%, cell number 100% of native values). SEM showed intact endothelial surfaces. Opening and closing behavior was sufficient under half of systemic conditions., Conclusions: The use of amniotic fluid as single cell source is a promising low-risk approach enabling the prenatal fabrication of heart valves ready to use at birth. These living replacements with the potential of growth, remodeling, and regeneration may realize the early repair of congenital malformations.

Valvular heart disease is still a significant cause of morbidity and mortality worldwide. Clinically used valve replacements including mechanical valves as well as fixed biological xeno- or homografts are associated with several major disadvantages. Alternatively, tissue engineering aims at the fabrication of autologous living cardiovascular replacements with the potential to grow and to repair, particularly for paediatric applications. Therefore, autologous cells are harvested and seeded onto three-dimensional matrices followed by biomimetic in vitro conditioning enabling the development of the neo-heart valve tissue. Here, we review different human cell sources such as vessels, bone marrow, umbilical cord tissue and blood, and chorionic villi with particular regard to cell phenotypes and their suitability for extracellular matrix production for tissue engineering purposes.

Heart valve replacement represents the most common surgical therapy for end-stage valvular heart diseases. A major drawback all contemporary heart valve replacements have in common is the lack of growth, repair, and remodeling capabilities. To overcome these limitations, the emerging field of tissue engineering is focusing on the in vitro generation of functional, living heart valve replacements. The basic approach uses starter matrices of either decellularized xenogeneic or biopolymeric materials configured in the shape of the heart valve and subsequent cell seeding. Moreover, in vitro strategies using mechanical loading in bioreactor systems have been developed to improve tissue maturation. This chapter gives a short overview of the current concepts and provides detailed methods for in vitro heart valve tissue engineering.

This study demonstrates the engineering of biologically active heart valve leaflets using prenatally available human umbilical cord-derived progenitor cells as the only cell source. Wharton's Jelly-derived cells and umbilical cord blood-derived endothelial progenitor cells were subsequently seeded on biodegradable scaffolds and cultured in a biomimetic system under biochemical or mechanical stimulation or both. Depending on the stimulation, leaflets showed mature layered tissue formation with functional endothelia and extracellular matrix production comparable with that of native tissues. This demonstrates the feasibility of heart valve leaflet fabrication from prenatal umbilical cord-derived progenitor cells as a further step in overcoming the lack of living autologous replacements with growth and regeneration potential for the repair of congenital malformation.

Valvular heart disease is still a significant cause of morbidity and mortality worldwide. Clinically used valve replacements including mechanical valves as well as fixed biological xeno- or homografts are associated with several major disadvantages. Alternatively, tissue engineering aims at the fabrication of autologous living cardiovascular replacements with the potential to grow and to repair, particularly for paediatric applications. Therefore, autologous cells are harvested and seeded onto three-dimensional matrices followed by biomimetic in vitro conditioning enabling the development of the neo-heart valve tissue. Here, we review different human cell sources such as vessels, bone marrow, umbilical cord tissue and blood, and chorionic villi with particular regard to cell phenotypes and their suitability for extracellular matrix production for tissue engineering purposes.

Background: Heart valve tissue engineering is a promising strategy to overcome the lack of autologous growing replacements, particularly for the repair of congenital malformations. Here, we present a novel concept using human prenatal progenitor cells as new and exclusive cell source to generate autologous implants ready for use at birth., Methods and Results: Human fetal mesenchymal progenitors were isolated from routinely sampled prenatal chorionic villus specimens and expanded in vitro. A portion was cryopreserved. After phenotyping and genotyping, cells were seeded onto synthetic biodegradable leaflet scaffolds (n=12) and conditioned in a bioreactor. After 21 days, leaflets were endothelialized with umbilical cord blood-derived endothelial progenitor cells and conditioned for additional 7 days. Resulting tissues were analyzed by histology, immunohistochemistry, biochemistry (amounts of extracellular matrix, DNA), mechanical testing, and scanning electron microscopy (SEM) and were compared with native neonatal heart valve leaflets. Fresh and cryopreserved cells showed comparable myofibroblast-like phenotypes. Genotyping confirmed their fetal origin. Neo-tissues exhibited organization, cell phenotypes, extracellular matrix production, and DNA content comparable to their native counterparts. Leaflet surfaces were covered with functional endothelia. SEM showed cellular distribution throughout the polymer and smooth surfaces. Mechanical profiles approximated those of native heart valves., Conclusions: Prenatal fetal progenitors obtained from routine chorionic villus sampling were successfully used as an exclusive, new cell source for the engineering of living heart valve leaflets. This concept may enable autologous replacements with growth potential ready for use at birth. Combined with the use of cell banking technology, this approach may be applied also for postnatal applications.

Background: Living autologous vascular grafts with the capacity for regeneration and growth may overcome the limitations of contemporary artificial prostheses. Particularly in congenital cardiovascular surgery, there is an unmet medical need for growing replacement materials. Here we investigate growth capacity of tissue-engineered living pulmonary arteries in a growing lamb model., Methods and Results: Vascular grafts fabricated from biodegradable scaffolds (ID 18+/-l mm) were sequentially seeded with vascular cells. The seeded constructs were grown in vitro for 21 days using biomimetic conditions. Thereafter, these tissue-engineered vascular grafts (TEVGs) were surgically implanted as main pulmonary artery replacements in 14 lambs using cardiopulmonary bypass and followed up for < or = 100 weeks. The animals more than doubled their body weight during the 2-year period. The TEVG showed good functional performance demonstrated by regular echocardiography at 20, 50, 80, and 100 weeks and computed tomography-angiography. In particular, there was no evidence of thrombus, calcification, stenosis, suture dehiscence, or aneurysm. There was a significant increase in diameter by 30% and length by 45%. Histology showed tissue formation reminiscent of native artery. Biochemical analysis revealed cellularity and proteoglycans and increased collagen contents in all of the groups, analogous to those of native vessels. The mechanical profiles of the TEVG showed stronger but less elastic tissue properties than native pulmonary arteries., Conclusions: This study provides evidence of growth in living, functional pulmonary arteries engineered from vascular cells in a full growth animal model.

Background: Ischemia/reperfusion injury (I/R) and cellular rejection in solid organ transplantation are characterized by adhesion molecule up-regulation on the graft endothelium, a prerequisite for leukocyte recruitment. The contribution of NK cells to I/R and allograft rejection is not well understood. The aim of the present study was to investigate allogeneic interactions between human NK cells and microvascular endothelial cells (MVEC) with special regard to the differential impact of TNF-alpha and hypoxia/reoxygenation in an in vitro model of I/R., Methods: MVEC were stimulated in vitro for 8 h with TNF-alpha, exposed to hypoxia (1% O2), hypoxia/reoxygenation, and combinations thereof in a hypoxia chamber. Cell surface expression of adhesion molecules on MVEC was analyzed by flow cytometry, and adhesion molecule shedding by ELISA. NK cell adhesion on MVEC was determined under shear stress, and NK cytotoxicity using Cr-release assays., Results: Surface expression of ICAM-1, VCAM-1, and E-/P-selectin on MVEC was up-regulated by TNF-alpha but unaffected by hypoxia/reoxygenation in the absence of TNF-alpha. ICAM-1 expression was further increased by a combination of TNF-alpha and hypoxia/reoxygenation, whereas TNF-alpha-induced E-/P-selectin expression was strongly reversed by hypoxia/reoxygenation. NK cell adhesion increased after exposing MVEC to TNF-alpha and hypoxia/reoxygenation. Susceptibility of MVEC to NK cytotoxicity was enhanced by TNF-alpha and slighty reduced by hypoxia/reoxygenation., Conclusions: Endothelial activation with TNF-alpha, but not hypoxia/reoxygenation, induced NK cytotoxicity whereas the combination thereof induced the strongest NK cell adhesion. Our findings suggesting a role for NK cells in allograft responses support the development of anti-inflammatory treatment strategies to prevent I/R.

Aim: Animal protection laws will lead to stricter and more selective criteria thus resulting in a decline of available animals. Yet to train cardiac surgical skills a totally artificial training model was developed., Description of the Training Model: The model is based on differently hardened polyurethane. Cover is a 1:1 replica of the human thoracic wall. Disposable coronaries are integrated in the heart-model. Vessels and part of the ascending aorta can be rinsed. By means of a newly designed air-pump stroke volume, heart-rate and rhythm can be adjusted., Experiences: Set-up of the model is easy and quick. Accustomed instruments can be used. Handling of artificial tissue is nature-like. Degree of difficulty is dependent on stroke volume, heart rate, arrhythmia, vessel-size and vessel-quality., Conclusion: The phantom helps to achieve confidence in coronary revascularisation. It facilitates an accompanying training for the less-trained as well as the skilled surgeon. The nature-like characteristics will help to reduce animal experiments in future.