| 1. |
- Grinnemo, Karl-Henrik, et al.
(author)
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Costimulation blockade induces tolerance to HESC transplanted to the testis and induces regulatory T-cells to HESC transplanted into the heart
- 2008
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In: Stem Cells. - : Oxford University Press (OUP). - 1549-4918 .- 1066-5099. ; 26:7, s. 1850-1857
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Journal article (peer-reviewed)abstract
- In order to study the ability of costimulation blockade to induce tolerance to human embryonic stem cells (HESC), severe combined immunodeficient (SCID), and immunocompetent C57BL/6 mice treated with costimulation blockade received intratesticular and intramyocardial HESC transplants. All SCID mice with intratesticular HESC transplants developed teratoma. When SCID mice were transplanted intramyocardially, only two of five mice developed teratoma-like tumors. C57BL/6 mice transplanted intratesticularly and treated with costimulation blockade all developed teratoma and were surrounded by CD4(+)CD25(+)Foxp3(+) T-cells, while isotype control treated recipients rejected their grafts. Most C57BL/6 mice transplanted intramyocardially and treated with costimulation blockade demonstrated lymphocytic infiltrates 1 month after transplantation, whereas one maintained its graft. Isolation of regulatory T-cells from intramyocardial transplanted recipients treated with costimulation blockade demonstrated specificity toward undifferentiated HESC and down-regulated naive T-cell activation toward HESC. These results demonstrate that costimulation blockade is sufficiently robust to induce tolerance to HESC in the immune-privileged environment of the testis. HESC specific regulatory T-cells developed to HESC transplanted to the heart and the success of transplantation was similar to that seen in SCID mice.
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| 2. |
- Simonson, Oscar E., et al.
(author)
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In Vivo Effects of Mesenchymal Stromal Cells in Two Patients With Severe Acute Respiratory Distress Syndrome
- 2015
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In: Stem Cells Translational Medicine. - : Oxford University Press (OUP). - 2157-6564 .- 2157-6580. ; 4:10, s. 1199-1213
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Journal article (peer-reviewed)abstract
- Mesenchymal stromal cells (MSCs) have been investigated as a treatment for various inflammatory diseases because of their immunomodulatory and reparative properties. However, many basic questions concerning their mechanisms of action after systemic infusion remain unanswered. We performed a detailed analysis of the immunomodulatory properties and proteomic profile of MSCs systemically administered to two patients with severe refractory acute respiratory distress syndrome (ARDS) on a compassionate use basis and attempted to correlate these with in vivo anti-inflammatory actions. Both patients received 2 x 10(6) cells per kilogram, and each subsequently improved with resolution of respiratory, hemodynamic, and multiorgan failure. In parallel, a decrease was seen in multiple pulmonary and systemic markers of inflammation, including epithelial apoptosis, alveolar-capillary fluid leakage, and proinflammatory cytokines, microRNAs, and chemokines. In vitro studies of the MSCs demonstrated a broad anti-inflammatory capacity, including suppression of T-cell responses and induction of regulatory phenotypes in T cells, monocytes, and neutrophils. Some of these in vitro potency assessments correlated with, and were relevant to, the observed in vivo actions. These experiences highlight both the mechanistic information that can be gained from clinical experience and the value of correlating in vitro potency assessments with clinical effects. The findings also suggest, but do not prove, a beneficial effect of lung protective strategies using adoptively transferred MSCs in ARDS. Appropriate randomized clinical trials are required to further assess any potential clinical efficacy and investigate the effects on in vivo inflammation. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:1199-1213
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| 3. |
- Wedin, Johan O, et al.
(author)
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Surgical Removal of a Detached Mitral Valve Repair Clip to Resolve Cardiogenic Shock
- 2022
-
In: JACC. - : Elsevier. - 2666-0849. ; 4:11, s. 658-662
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Journal article (peer-reviewed)abstract
- Transcatheter edge-to-edge mitral valve repair (TEER) with a clip device relieves symptoms and improves outcomes in patients not suitable for open heart surgery. Here, we present a patient in whom ventricular arrhythmias developed as a result of clip embolization shortly after TEER. He underwent successful emergent surgical clip removal and mitral valve replacement. (Level of Difficulty: Advanced.).
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| 4. |
- Ahlgren, Bengt, et al.
(author)
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Are MIRCC and Rate-based Congestion Control in ICN READY for Variable Link Capacity?
- 2017
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Conference paper (other academic/artistic)abstract
- Information-centric networking (ICN) has been introduced as a potential future networking architecture. ICN promises an architecture that makes information independent from lo- cation, application, storage, and transportation. Still, it is not without challenges. Notably, there are several outstanding issues regarding congestion control: Since ICN is more or less oblivious to the location of information, it opens up for a single application flow to have several sources, something which blurs the notion of transport flows, and makes it very difficult to employ traditional end-to-end congestion control schemes in these networks. Instead, ICN networks often make use of hop-by-hop congestion control schemes. How- ever, these schemes are also tainted with problems, e.g., several of the proposed ICN congestion controls assume fixed link capacities that are known beforehand. Since this seldom is the case, this paper evaluates the consequences in terms of latency, throughput, and link usage, variable link capacities have on a hop-by-hop congestion control scheme, such as the one employed by the Multipath-aware ICN Rate-based Congestion Control (MIRCC). The evaluation was carried out in the OMNeT++ simulator, and demonstrates how seemingly small variations in link capacity significantly deterio- rate both latency and throughput, and often result in inefficient network link usage.
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| 5. |
- Ahlgren, Bengt, et al.
(author)
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ICN congestion control for wireless links
- 2018
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In: IEEE WCNC 2018 Conference Proceedings. - New York : IEEE.
-
Conference paper (peer-reviewed)abstract
- Information-centric networking (ICN) with its design around named-based forwarding and in-network caching holds great promises to become a key architecture for the future Internet. Many proposed ICN hop-by-hop congestion control schemes assume a fixed and known link capacity, which rarely - if ever - holds true for wireless links. Firstly, we demonstrate that although these congestion control schemes are able to fairly well utilise the available wireless link capacity, they greatly fail to keep the delay low. In fact, they essentially offer the same delay as in the case with no hop-by-hop, only end-to-end, congestion control. Secondly, we show that by complementing these schemes with an easy-to-implement, packet-train capacity estimator, we reduce the delay to a level significantly lower than what is obtained with only end-to-end congestion control, while still being able to keep the link utilisation at a high level.
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| 6. |
- Ahlgren, Bengt, et al.
(author)
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Latency-aware Multipath Scheduling inInformation-centric Networks
- 2019
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In: Proceedings of the Fifteenth Swedish National Computer Networking Workshop (SNCNW), Luleå, Sweden. 4-5 June 2019..
-
Conference paper (peer-reviewed)abstract
- We present the latency-aware multipath schedulerZQTRTT that takes advantage of the multipath opportunities ininformation-centric networking. The goal of the scheduler is touse the (single) lowest latency path for transaction-oriented flows,and use multiple paths for bulk data flows. A new estimatorcalled zero queue time ratio is used for scheduling over multiplepaths. The objective is to distribute the flow over the paths sothat the zero queue time ratio is equal on the paths, that is,so that each path is ‘pushed’ equally hard by the flow withoutcreating unwanted queueing. We make an initial evaluation usingsimulation that shows that the scheduler meets our objectives.
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| 7. |
- Aldi, Silvia, et al.
(author)
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Dual roles of heparanase in human carotid plaque calcification
- 2019
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In: Atherosclerosis. - : ELSEVIER IRELAND LTD. - 0021-9150 .- 1879-1484. ; 283, s. 127-136
-
Journal article (peer-reviewed)abstract
- Background and aims: Calcification is a hallmark of advanced atherosclerosis and an active process akin to bone remodeling. Heparanase (HPSE) is an endo-beta-glucuronidase, which cleaves glycosaminoglycan chains of heparan sulfate proteoglycans. The role of HPSE is controversial in osteogenesis and bone remodeling while it is unexplored in vascular calcification. Previously, we reported upregulation of HPSE in human carotid endarterectomies from symptomatic patients and showed correlation of HPSE expression with markers of inflammation and increased thrombogenicity. The present aim is to investigate HPSE expression in relation to genes associated with osteogenesis and osteolysis and the effect of elevated HPSE expression on calcification and osteolysis in vitro.Methods: Transcriptomic and immunohistochemical analyses were performed using the Biobank of Karolinska Endarterectomies (BiKE). In vitro calcification and osteolysis were analysed in human carotid smooth muscle cells overexpressing HPSE and bone marrow-derived osteoclasts from HPSE-transgenic mice respectively.Results: HPSE expression correlated primarily with genes coupled to osteoclast differentiation and function in human carotid atheromas. HPSE was expressed in osteoclast-like cells in atherosclerotic lesions, and HPSE-transgenic bone marrow-derived osteoclasts displayed a higher osteolytic activity compared to wild-type cells. Contrarily, human carotid SMCs with an elevated HPSE expression demonstrated markedly increased mineralization upon osteogenic differentiation.Conclusions: We suggest that HPSE may have dual functions in vascular calcification, depending on the stage of the disease and presence of inflammatory cells. While HPSE plausibly enhances mineralization and osteogenic differentiation of vascular smooth muscle cells, it is associated with inflammation-induced osteoclast differentiation and activity in advanced atherosclerotic plaques.
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| 8. |
- Beljanski, Vladimir, et al.
(author)
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Pleiotropic roles of autophagy in stem cell-based therapies
- 2019
-
In: Cytotherapy. - : ELSEVIER SCI LTD. - 1465-3249 .- 1477-2566. ; 21:4, s. 380-392
-
Research review (peer-reviewed)abstract
- Stem cells (SCs) have been proven to possess regenerative and immunomodulatory properties and can be used to treat diseases that involve loss of cells due to tissue damage or inflammation. For this approach to succeed, SCs or their derivatives should be able to engraft in the target tissue at least for a short period of time. Unfortunately, once injected, therapeutic SCs will encounter a hostile environment, including hypoxia, lack of nutrients and stromal support, and cells may also be targeted and rejected by the immune system. Therefore, SC's stress-response mechanisms likely play a significant role in survival of injected cells and possibly contribute to their therapeutic efficacy. Autphagy, a stress-response pathway, is involved in many different cellular processes, such as survival during hypoxia and nutrient deprivation, cellular differentiation and de-differentiation, and it can also contribute to their immunovisibility by regulating antigen presentation and cytokine secretion. Autophagy machinery interacts with many proteins and signaling pathways that regulate SC properties, including PI3K/Akt, mammalian target of rapamycin (mTOR), Wnt, Hedgehog and Notch, and it is also involved in regulating intracellular reactive oxygen species (ROS) levels. In this review, we contend that autophagy is an important therapeutic target that can be used to improve the outcome of SC-based tissue repair and regeneration. Further research should reveal whether inhibition or stimulation of autophagy increases the therapeutic utility of SCs and it should also identify appropriate therapeutic regimens that can be applied in the clinic.
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| 9. |
- Beusch, Christian M., et al.
(author)
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Analysis of local extracellular matrix identifies different aetiologies behind bicuspid and tricuspid aortic valve degeneration and suggests therapies
- 2023
-
In: Cellular and Molecular Life Sciences (CMLS). - : Springer Nature. - 1420-682X .- 1420-9071. ; 80:9
-
Journal article (peer-reviewed)abstract
- Aortic valve degeneration (AVD) is a life-threatening condition that has no medical treatment and lacks individual therapies. Although extensively studied with standard approaches, aetiologies behind AVD are unclear. We compared abundances of extracellular matrix (ECM) proteins from excised valve tissues of 88 patients with isolated AVD of normal tricuspid (TAV) and congenital bicuspid aortic valves (BAV), quantified more than 1400 proteins per ECM sample by mass spectrometry, and demonstrated that local ECM preserves molecular cues of the pathophysiological processes. The BAV ECM showed enrichment with fibrosis markers, namely Tenascin C, Osteoprotegerin, and Thrombospondin-2. The abnormal physical stress on BAV may cause a mechanical injury leading to a continuous Tenascin C-driven presence of myofibroblasts and persistent fibrosis. The TAV ECM exhibited enrichment with Annexin A3 (p = 1.1 x 10(-16) and the fold change 6.5) and a significant deficit in proteins involved in high-density lipid metabolism. These results were validated by orthogonal methods. The difference in the ECM landscape suggests distinct aetiologies between AVD of BAV and TAV; warrants different treatments of the patients with BAV and TAV; elucidates the molecular basis of AVD; and implies possible new therapeutic approaches. Our publicly available database (human_avd_ecm.surgsci. uu.se) is a rich source for medical doctors and researchers who are interested in AVD or heart ECM in general. Systematic proteomic analysis of local ECM using the methods described here may facilitate future studies of various tissues and organs in development and disease.
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| 10. |
- Christoforidis, Christos, et al.
(author)
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SCTPTrace : An Extension of TCPTrace for SCTP
- 2016
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Reports (pop. science, debate, etc.)abstract
- When it comes to analyzing TCP data and extracting the information in such a way that it becomes viewable, there are a couple of tools that can be used. One of them is TCPTrace. TCPTrace is used to analyze special dump files created from programs such as tcpdump, snoop and WinDump. TCPTrace became published for a broader public in the late 1996 by Shawn Ostermann. Since then functionalities, changes and fixes have been implemented for example the extension to create graphs and trace UDP packets. From the dump files a trace will be done, and depending on the input from the user, TCPTrace can present this information in a number of ways such as plain text, trace files and graphs, depending on the amount of information the user is looking for. The extensive information traced will be viewed and divided for each connection found. For each connection, information such as retransmits, throughput, round trip times, bytes and packets sent and received etc. can be presented.This project came to be, since there has been a desire to see a tool for SCTP that provides the same functionalities as TCPTrace. The project, called SCTPTrace, aimed to implement as much of the previous TCP functionalities as possible for the SCTP protocol.
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| 11. |
- Dalen, Magnus, et al.
(author)
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Percutaneous Fluoroscopic-Guided Endomyocardial Delivery in an Experimental Model of Left Ventricular Assist Device Support
- 2015
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In: Journal of Cardiovascular Translational Research. - : Springer Science and Business Media LLC. - 1937-5387 .- 1937-5395. ; 8:6, s. 381-384
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Journal article (peer-reviewed)abstract
- Endomyocardial delivery in the setting of active left ventricular assist device (LVAD) support has rarely been studied. The objective was to establish a protocol for endomyocardial injections during LVAD support without compromising mechanical circulation. LVAD implantation was performed in four pigs. A curved needle catheter was percutaneously inserted into the right carotid artery and positioned into the left ventricle under fluoroscopic guidance. In the setting of increasing LVAD flows (2.3-3.1 l/min), percutaneous methylene blue dye administration into the myocardium proceeded without complications in all pigs. Transection of excised hearts revealed an anterior, lateral, inferior, and septal wall distribution of methylene blue documenting injections in all four regions of the left ventricle. Ex vivo, the catheter could be maneuvered close to the LVAD inflow cannula despite augmentation of LVAD flow up to 5 l/min. Endomyocardial injections during LVAD support was found to be feasible and safe with the curved needle catheter.
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| 12. |
- Danielsson, Christian, et al.
(author)
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Exploration of human, rat, and rabbit embryonic cardiomyocytes suggests K-channel block as a common teratogenic mechanism
- 2013
-
In: Cardiovascular Research. - : Oxford University Press (OUP): Policy B. - 0008-6363 .- 1755-3245. ; 97:1, s. 23-32
-
Journal article (peer-reviewed)abstract
- Several drugs blocking the rapidly activating potassium (K-r) channel cause malformations (including cardiac defects) and embryonic death in animal teratology studies. In humans, these drugs have an established risk for acquired long-QT syndrome and arrhythmia. Recently, associations between cardiac defects and spontaneous abortions have been reported for drugs widely used in pregnancy (e.g. antidepressants), with long-QT syndrome risk. To investigate whether a common embryonic adverse-effect mechanism exists in the human, rat, and rabbit embryos, we made a comparative study of embryonic cardiomyocytes from all three species. less thanbrgreater than less thanbrgreater thanPatch-clamp and quantitative-mRNA measurements of K-r and slowly activating K (K-s) channels were performed on human, rat, and rabbit primary cardiomyocytes and cardiac samples from different embryo-foetal stages. The K-r channel was present when the heart started to beat in all species, but was, in contrast to human and rabbit, lost in rats in late organogenesis. The specific K-r-channel blocker E-4031 prolonged the action potential in a species- and development-dependent fashion, consistent with the observed K-r-channel expression pattern and reported sensitive periods of developmental toxicity. E-4031 also increased the QT interval and induced 2:1 atrio-ventricular block in multi-electrode array electrographic recordings of rat embryos. The K-s channel was expressed in human and rat throughout the embryo-foetal period but not in rabbit. less thanbrgreater than less thanbrgreater thanThis first comparison of mRNA expression, potassium currents, and action-potential characteristics, with and without a specific K-r-channel blocker in human, rat, and rabbit embryos provides evidence of K-r-channel inhibition as a common mechanism for embryonic malformations and death.
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| 13. |
- Fux, Thomas, et al.
(author)
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Synthetic tracheal grafts seeded with bone marrow cells fail to generate functional tracheae : First long-term follow-up study
- 2020
-
In: Journal of Thoracic and Cardiovascular Surgery. - : MOSBY-ELSEVIER. - 0022-5223 .- 1097-685X. ; 159:6, s. 2525-2537.e23
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Journal article (peer-reviewed)abstract
- Objective: Synthetic tracheal grafts seeded with autologous bone marrow-mononuclear cells (BM-MNCs) have been described as becoming living and functional grafts representing a promising option for tracheal replacement for pathologies unamenable by segmental resection or autologous repair. This study aimed to present the first long-term follow-up of these procedures in humans.Methods: We retrospectively analyzed 3 patients who received synthetic tracheal grafts seeded with BM-MNCs implanted.Results: Patient 1 was a 37-year-old man with mucoepidermoid carcinoma, the first-ever human to receive a synthetic tracheal graft seeded with BM-MNCs. Patient 2 was a 30-year-old man with adenoid cystic carcinoma, and patient 3 was a 22-year-old woman with an iatrogenic tracheal injury. All patients developed graft-related complications necessitating multiple surgical reinterventions. Patient 1 was hospitalized for 8 months before dying from respiratory failure secondary to graft dehiscence 32 months after implantation. Patient 2 died 3.5 months after implantation from undisclosed causes. Patient 3 received a second synthetic tracheal graft after 11 months and an allogeneic trachea and lung transplantation 45 months after the primary implantation. Patient 3 underwent 191 surgical interventions after the primary implantation and spent 55 months in the intensive care unit before dying from airway bleeding. All patients' bronchoscopic, histologic, and radiologic investigations demonstrated graft-associated complications, including anastomotic fistulae and obstructive granulation tissue, without graft vascularization, mucosal lining, or integration into adjacent tissues.Conclusions: Synthetic tracheal grafts seeded with BM-MNCs do not become living functional tracheal grafts and lead to debilitating complications and death.
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| 14. |
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| 15. |
- Granath, Carl, et al.
(author)
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Characterization of Laminins in Healthy Human Aortic Valves and a Modified Decellularized Rat Scaffold
- 2020
-
In: BioResearch Open Access. - : Mary Ann Liebert. - 2164-7844 .- 2164-7860. ; 9:1, s. 269-278
-
Journal article (peer-reviewed)abstract
- Aortic valve stenosis is one of the most common cardiovascular diseases in western countries and can only be treated by replacement with a prosthetic valve. Tissue engineering is an emerging and promising treatment option, but in-depth knowledge about the microstructure of native heart valves is lacking, making the development of tissue-engineered heart valves challenging. Specifically, the basement membrane (BM) of heart valves remains incompletely characterized, and decellularization protocols that preserve BM components are necessary to advance the field. This study aims to characterize laminin isoforms expressed in healthy human aortic valves and establish a small animal decellularized aortic valve scaffold for future studies of the BM in tissue engineering. Laminin isoforms were assessed by immunohistochemistry with antibodies specific for individual alpha, beta, and gamma chains. The results indicated that LN-411, LN-421, LN-511, and LN-521 are expressed in human aortic valves (n = 3), forming a continuous monolayer in the endothelial BM, whereas sparsely found in the interstitium. Similar results were seen in rat aortic valves (n = 3). Retention of laminin and other BM components, concomitantly with effective removal of cells and residual DNA, was achieved through 3 h exposure to 1% sodium dodecyl sulfate and 30 min exposure to 1% Triton X-100, followed by nuclease processing in rat aortic valves (n = 3). Our results provide crucial data on the microenvironment of valvular cells relevant for research in both tissue engineering and heart valve biology. We also describe a decellularized rat aortic valve scaffold useful for mechanistic studies on the role of the BM in heart valve regeneration.
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| 16. |
- Grinnemo, Karl-Henrik
(author)
-
Cell transplantation with human mesenchymal or embryonic stem cells to the heart : experimental, molecular, immunological and echocardiographic studies
- 2007
-
Doctoral thesis (other academic/artistic)abstract
- Background: Human mesenchymal stem cells (hMSC), human embryonic stem cells (HESC) and human fetal cardiomyocyte progenitor cells (HFCP) all represent possible candidate cells for regeneration of damaged myocardium. Although they represent cell types with many positive attributes, their capacity to engraft, to differentiate into mature cardiomyocytes, to improve myocardial function and their immunological properties are the focus of these studies. Methods and Results: hMSC were rejected from the myocardium of immunocompetent rats even if immunosuppression with Tacrolimus was used. Re-exposure of hMSC to lymphocytes from rats previously exposed to hMSC caused a significant proliferation indicating a sensitization reaction. The hMSC survived in the myocardium of athymic T-cell deficient rats and in an ischemic rat model the survival of the hMSC increased when Tacrolimus was added. Even though the hMSC survived in the ischemic myocardium they did not differentiate into cardiomyocytes or improve the myocardial function. HESC have the ability to differentiate into cardiomyocytes, but a major obstacle to clinical application is their immunological characteristics. We have shown that HESC express HLA class I, no HLA class II and low levels of costimulatory molecules. HESC are immunologically inert and do not inhibit immune responses during direct or indirect antigen presentation and HESC were acutely rejected when transplanted over the xenogeneic barrier into mice. In order to study the possibility to induce tolerance towards in vivo differentiating HESC, these were implanted into the testis and heart of immunocompetent mice treated with costimulation blockade. The HESC developed into teratoma in the testis in all mice and induced regulatory T-cells to undifferentiated HESC when transplanted into the heart. When costimulation blockade was repeated HESC engrafted in the myocardium in one of five mice. Islet-1 positive cells were identified in the atria and outflow tracts of aborted human fetal hearts. We succeeded to isolate and culture the Islet-1 positive cells and their progeny in a reproducible manner, forming spontaneously beating cardiospheres and monolayers. Implantation of the HFCP formed stable engraftments in the myocardium of SCID mice. Conclusions: hMSC are immunogenic in xenogeneic settings and they do not improve myocardial function or differentiate into cardiomyocytes in a rat ischemia model. HESC are also immunogenic in allogeneic and xenogeneic settings. Costimulation blockade is sufficiently robust to induce tolerance to HESC in an immune-privileged environment like testis. HESC transplanted into the myocardium of immunocompetent mice induced regulatory T-cells and when the costimulation blockade was repeated the success of transplantation was similar to that seen in SCID mice. The cardiomyocyte origin of the HFCP, their capacity to grow in culture and their formation of stable engraftments in the myocardium make the HFCP a putative candidate for cardiomyoplasty.
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| 17. |
- Grinnemo, Karl-Henrik, et al.
(author)
-
Immunomodulatory effects of interferon-gamma on human fetal cardiac mesenchymal stromal cells
- 2019
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In: Stem Cell Research & Therapy. - : BMC. - 1757-6512. ; 10
-
Journal article (peer-reviewed)abstract
- Background: Mesenchymal stromal cells (MSCs), due to their regenerative and immunomodulatory properties, are therapeutically used for diseases, including heart failure. As early gestational-phase embryonic tissues exhibit extraordinary regenerative potential, fetal MSCs exposed to inflammation offer a unique opportunity to evaluate molecular mechanisms underlying preferential healing, and investigate their inherent abilities to communicate with the immune system during development. The principal aim of this study was to evaluate the effects of interferon-gamma (IFN gamma) on the immunomodulatory effects of first-trimester human fetal cardiac (hfc)-MSCs.Methods: hfcMSCs (gestational week 8) were exposed to IFN gamma, with subsequent analysis of the whole transcriptome, based on RNA sequencing. Exploration of surface-expressed immunoregulatory mediators and modulation of T cell responses were performed by flow cytometry. Presence and activity of soluble mediators were assessed by ELISA or high-performance liquid chromatography.Results: Stimulation of hfcMSCs with IFN gamma revealed significant transcriptional changes, particularly in respect to the expression of genes belonging to antigen presentation pathways, cell cycle control, and interferon signaling. Expression of immunomodulatory genes and associated functional changes, including indoleamine 2,3-dioxygenase activity, and regulation of T cell activation and proliferation via programmed cell death protein (PD)-1 and its ligands PD-L1 and PD-L2, were significantly upregulated. These immunoregulatory molecules diminished rapidly upon withdrawal of inflammatory stimulus, indicating a high degree of plasticity by hfcMSCs.Conclusions: To our knowledge, this is the first study performing a systematic evaluation of inflammatory responses and immunoregulatory properties of first-trimester cardiac tissue. In summary, our study demonstrates the dynamic responsiveness of hfcMSCs to inflammatory stimuli. Further understanding as to the immunoregulatory properties of hfcMSCs may be of benefit in the development of novel stromal cell therapeutics for cardiovascular disease.
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| 18. |
- Hao, Xiaojin, et al.
(author)
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Angiogenic effects of sequential release of VEGF-A(165) and PDGF-BB with alginate hydrogels after myocardial infarction
- 2007
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In: Cardiovascular Research. - : Oxford University Press (OUP). - 0008-6363 .- 1755-3245. ; 28, s. 612-612
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Journal article (peer-reviewed)abstract
- Objective: This study investigates whether local sequential delivery of vascular endothelial growth factor-A(165) (VEGF-A(165)) followed by platelet-derived growth factor-BB (PDGF-BB) with alginate hydrogels could induce an angiogenic effect and functional improvement greater than single factors after myocardial infarction. Methods: Alginate hydrogels were prepared by combining high and low molecular weight alginate. Growth factor release rates were monitored over time in vitro with I-125-labelled VEGF-A(165) and PDGF-BB included in the gels. One week after myocardial infarction was induced in Fisher rats, gels with VEGF-A(165), PDGF-BB, or both were given intra-myocardially along the border of the myocardial infarction. Vessel density was analysed in hearts and cardiac function was determined by Tissue Doppler Echocardiography. In addition, the angiogenic effect of sequenced delivery was studied in vitro in aortic rings from C57B1/6 mice. Results: Alginate gets were capable of delivering VEGF-A(165) and PDGF-BB in a sustainable manner, and PDGF-BB was released more slowly than VEGF-A(165). Sequential growth factor administration led to a higher density of alpha-actin positive vessels than single factors, whereas no further increment was found in capillary density. Sequential protein delivery increased the systolic velocity-time integral and displayed a superior effect than single factors. In the aortic ring model, sequential delivery led to a higher angiogenic effect than single factor administration. Conclusions: The alginate hydrogel is an effective and promising injectable delivery system in a myocardial infarction model. Sequential growth factor delivery of VEGF-A(165) and PDGF-BB induces mature vessels and improves cardiac function more than each factor singly. This may indicate clinical utility.
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| 19. |
- Hao, Xiaojin, et al.
(author)
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Myocardial angiogenesis after plasmid or adenoviral VEGF-A(165) gene transfer in rat myocardial infarction model
- 2007
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In: Cardiovascular Research. - : Oxford University Press (OUP). - 0008-6363 .- 1755-3245. ; 73:3, s. 481-487
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Journal article (peer-reviewed)abstract
- Objective: To compare gene transfer of plasmid (P) and adenovirus (Ad) encoding human vascular endothelial growth factor-A(165) (hVEGF-A(165)) angiogenic efficacy and adverse effects as regards apoptosis and ectopic expression of the transgene in a rat myocardial infarction model. Methods: Myocardial infarction was provoked in Fisher rats. One week later, PhVEGF-A(165), PLacZ, AdhVEGF-A(165), or AdLacZ was transferred intramyocardially along the border of the myocardial infarction. hVEGF-A expression was detected with ELISA. Myocardial vessel density was analyzed 1 and 4 weeks after gene transfer. Apoptosis was detected by TUNEL staining. Cardiac function was assessed with Tissue Doppler Velocity Imaging. Results: Although AdhVEGF-A(165) had substantially higher myocardial hVEGF-A expression than PhVEGF-A(165), AdhVEGF-A(165) and PhVEGF-A(165) induced angiogenic effects to a similar extent with maintained increased arteriolar density after 4 weeks of gene transfer (p < 0.05). The two treatments also improved left ventricular function similarly. Adenoviral gene transfer induced a higher number of TUNEL positive cells than plasmid (p < 0.02). Ectopic expression of the transgene was present with both vectors but substantially higher after adenoviral gene transfer. Conclusions: AdhVEGF-A165 has no obvious angiogenic advantage over PhVEGF-A165 but more side effects at least in a rat myocardial infarction model. This indicates that PhVEGF-A(165) might be more applicable for therapeutic angiogenesis than AdhVEGF-A(165).
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| 20. |
- Jungebluth, Philipp, et al.
(author)
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Tracheobronchial transplantation with a stem-cell-seeded bioartificial nanocomposite : a proof-of-concept study
- 2011
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In: The Lancet. - 0140-6736 .- 1474-547X. ; 378:9808, s. 1997-2004
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Journal article (peer-reviewed)abstract
- Background Tracheal tumours can be surgically resected but most are an inoperable size at the time of diagnosis; therefore, new therapeutic options are needed. We report the clinical transplantation of the tracheobronchial airway with a stem-cell-seeded bioartificial nanocomposite. Methods A 36-year-old male patient, previously treated with debulking surgery and radiation therapy, presented with recurrent primary cancer of the distal trachea and main bronchi. After complete tumour resection, the airway was replaced with a tailored bioartificial nanocomposite previously seeded with autologous bone-marrow mononuclear cells via a bioreactor for 36 h. Postoperative granulocyte colony-stimulating factor filgrastim (10 mu g/kg) and epoetin beta (40 000 UI) were given over 14 days. We undertook flow cytometry, scanning electron microscopy, confocal microscopy epigenetics, multiplex, miRNA, and gene expression analyses. Findings We noted an extracellular matrix-like coating and proliferating cells including a CD105+ subpopulation in the scaffold after the reseeding and bioreactor process. There were no major complications, and the patient was asymptomatic and tumour free 5 months after trans plantation. The bioartificial nanocomposite has patent anastomoses, lined with a vascularised neomucosa, and was partly covered by nearly healthy epithelium. Post-operatively, we detected a mobilisation of peripheral cells displaying increased mesenchymal stromal cell phenotype, and upregulation of epoetin receptors, antiapoptotic genes, and miR-34 and miR-449 biomarkers. These findings, together with increased levels of regenerative-associated plasma factors, strongly suggest stem-cell homing and cell-mediated wound repair, extracellular matrix remodelling, and neovascularisation of the graft. Interpretation Tailor-made bioartificial scaffolds can be used to replace complex airway defects. The bioreactor reseeding process and pharmacological-induced site-specific and graft-specific regeneration and tissue protection are key factors for successful clinical outcome.
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| 21. |
- Ljung, Karin, et al.
(author)
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Human Fetal Cardiac Mesenchymal Stromal Cells Differentiate In Vivo into Endothelial Cells and Contribute to Vasculogenesis in Immunocompetent Mice
- 2019
-
In: Stem Cells and Development. - : MARY ANN LIEBERT, INC. - 1547-3287 .- 1557-8534. ; 28:5, s. 310-318
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Journal article (peer-reviewed)abstract
- Mesenchymal stromal cells (MSCs) have shown great potential as a treatment for systemic inflammatory diseases, but their local regenerative properties are highly tissue- and site specific. Previous studies have demonstrated that adult human MSCs respond to inflammatory cytokines through the release of paracrine factors that stimulate angiogenesis, but they do not themselves differentiate into vascular structures in vivo. In this study, we used human fetal cardiac MSCs (hfcMSCs) harvested during the first trimester of heart development and injected them into the subcutaneous tissue of normal immunocompetent mice treated with short-term costimulation blockade for tolerance induction. When hfcMSCs were transplanted subcutaneously together with Matrigel matrix, they contributed to vasculogenesis through differentiation into endothelial cells and generation of the basal membrane protein Laminin 4. These characteristics of hfcMSCs are similar to the mesodermal progenitors giving rise to the developing heart and they may be useful for treatment of ischemic injuries.
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| 22. |
- Nilsson Ekdahl, Kristina, et al.
(author)
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Therapeutic regulation of complement activation in extracorporeal circuits and intravascular treatments with special reference to the alternative pathway amplification loop
- 2023
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In: Immunological Reviews. - : John Wiley & Sons. - 0105-2896 .- 1600-065X. ; 313:1, s. 91-103
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Journal article (peer-reviewed)abstract
- A number of clinical treatment modalities involve contact between blood and biomaterials: these include extracorporeal circuits such as hemodialysis, cardiopulmonary bypass, plasmapheresis, and intravascular treatments. Common side effects arising from these treatments are caused by activation of the cascade systems of the blood. Many of these side effects are mediated via the complement system, including thromboinflammatory reactions and rejection of implants. Depending on the composition of the materials, complement activation is triggered via all the activation pathways but is by far mostly driven by the alternative pathway amplification loop. On biomaterial surfaces the alternative pathway amplification is totally unregulated and leads under optimal conditions to deposition of complement fragments, mostly C3b, on the surface leading to a total masking of the underlying surface. In this review, we discuss the mechanism of the complement activation, clinical consequences of the activation, and potential strategies for therapeutic regulation of the activation, using hemodialysis as demonstrator.
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| 23. |
- Olesen, Kim, et al.
(author)
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Diversity of respiratory parameters and metabolic adaptation to low oxygen tension in mesenchymal stromal cells
- 2022
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In: Metabolism Open. - : Elsevier. - 2589-9368. ; 13:March
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Journal article (peer-reviewed)abstract
- ObjectiveCell metabolism has been shown to play an active role in regulation of stemness and fate decision. In order to identify favorable culture conditions for mesenchymal stromal cells (MSCs) prior to transplantation, this study aimed to characterize the metabolic function of MSCs from different developmental stages in response to different oxygen tension during expansion.Materials and methodsWe cultured human fetal cardiac MSCs and human adult bone-marrow MSCs for a week under hypoxia (3% O2) and normoxia (20% O2). We performed mitochondrial characterization and assessed oxygen consumption- and extracellular acidification-rates (OCR and ECAR) in addition to oxygen-sensitive respiration and mitochondrial complex activities, using both the Seahorse and Oroboros systems.ResultsAdult and fetal MSCs displayed similar basal respiration and mitochondrial amount, however fetal MSCs had lower spare respiratory capacity and apparent coupling efficiency. Fetal MSCs expanded in either hypoxia or normoxia demonstrated similar acidification rates, while adult MSCs downregulated their aerobic glycolysis in normoxia. Acute decrease in oxygen tension caused a higher respiratory inhibition in adult compared to fetal MSCs. In both sources of MSCs, minor changes in complex activities in normoxic and hypoxic cultures were found.ConclusionsIn contrast to adult MSCs, fetal MSCs displayed similar respiration and aerobic glycolysis at different O2 culture concentrations during expansion. Adult MSCs adjusted their respiration to glycolytic activities, depending on the culture conditions thus displaying a more mature metabolic function. These findings are relevant for establishing optimal in vitro culturing conditions, with the aim to maximize engraftment and therapeutic outcome.
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| 24. |
- Olesen, Kim
(author)
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Extracellular factors for preservation and delivery of stromal cells
- 2021
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Doctoral thesis (other academic/artistic)abstract
- Modulating the immune response after a myocardial infarction seems like an appropriate strategy for reducing myocardial fibrosis. Mesenchymal Stromal Cells are immunomodulatory and have thus gained interest, but have so far not achieved the desired clinical outcomes. This is believed to due to the loss of their immunomodulatory and proliferative capacity during expansion and poor cell survival and retention upon delivery to the myocardium. The use of extracellular factors such as extracellular matrices, paracrine factors, nutrients as well as manipulation gas composition during culture might be used to overcome some of these shortcomings, which is further explored in this thesis.We demonstrated in Study I, that encapsulation of human cells by thermos-responsive microcapsules, which upon exposure to physiological temperature partially decompose and enable release of the cells. The hydrogel combination of agarose, gelatin and fibrinogen provided both thermos-responsive features and attachment points for the cells, preventing cell death. However, additional components can be used to support the encapsulated cells while retaining the thermo-responsiveness. In order to discover such components, we developed an in vitro model to study the cell- and extracellular matrix dynamics making use of the organ’s extracellular matrix and define anatomical regions that are capable of retaining the desired phenotype of the cell. To generate such a syngeneic model, naïve stromal cells were isolated from fetal rat hearts, and cultured on decellularized extracellular matrix sections of adult rat hearts. We found that when culturing cells with pericyte-like characteristics on the matrices, the surface marker expressions of CD146 and PDGFR-β were depending on the matrix composition, and especially of laminin alpha 4. Cells expressing CD146 were mainly located to the atrioventricular junction and to the perivascular niche, while PDGFR-β expression was more widespread. Since CD146 is also a potency marker for Mesenchymal Stromal Cells, these results indicate a matrix dependent niche for naïve stromal cells. These findings were next verified by immunohistochemistry of the native rat heart, where CD146 populations were mainly found in the atrioventricular and perivascular niche.In Study III, we explored the preferred metabolism of adult and fetal MSCs. It is known that proliferating stem-, progenitor cells utilize glycolysis, even in presence of oxygen. Therefore, we wanted to explore the metabolic profiles of human fetal (naïve) and MSCs during culture in either hypoxia 3% (close to physiological oxygen tension) or normoxia 20%. Adult MSCs grown in hypoxia retained oxidative phosphorylation and increased glycolytic activity, adapting a progenitor metabolic profile while in normoxia the adult MSCs down-regulated glycolysis and adapted an adult, or differentiated cell metabolic profile. Fetal MSCs demonstrated preserved oxidative phosphorylation and glycolytic activity regardless of oxygen tension, thus exhibiting a stem-, progenitor metabolic profile.The findings from these studies might help in designing future culture protocols and delivery systems for cell therapies.
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| 25. |
- Olesen, Kim, et al.
(author)
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Spatiotemporal extracellular matrix modeling for in situ cell niche studies
- 2021
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In: Stem Cells. - : John Wiley & Sons. - 1066-5099 .- 1549-4918. ; 39:12, s. 1751-1765
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Journal article (peer-reviewed)abstract
- Extracellular matrix (ECM) components govern a range of cell functions such as migration, proliferation, maintenance of stemness and differentiation. Cell niches that harbor stem-/progenitor cells, with matching ECM, have been shown in a range of organs, although their presence in the heart is still under debate. Determining niches depends on a range of in vitro and in vivo models and techniques, where animal models are powerful tools for studying cell-ECM dynamics, however, they are costly and time-consuming to use. In vitro models based on recombinant ECM proteins lack the complexity of the in vivo ECM. To address these issues, we present the Spatiotemporal Extracellular Matrix Model (StEMM) for studies of cell-ECM dynamics, such as cell niches. This model combines gentle decellularization and sectioning of cardiac tissue, allowing retention of a complex ECM, with recellularization and subsequent image processing using image stitching, segmentation, automatic binning and generation of cluster maps. We have thereby developed an in situ representation of the cardiac ECM that is useful for assessment of repopulation dynamics and to study the effect of local ECM composition on phenotype preservation of reseeded mesenchymal progenitor cells. This model provides a platform for studies of organ-specific cell-ECM dynamics and identification of potential cell niches. © AlphaMed Press 2021 SIGNIFICANCE STATEMENT: Stem cells reside in adult organs within specific microenvironments called cell niches. The heart is a complex organ and so far, the presence and localization of stem-/progenitor cell niches are subject to constant debate. To address these issues, the authors have developed the Spatiotemporal Extracellular Matrix Model (StEMM), which combines a modified protocol for decellularization, with cryo-sectioning, recellularization, and subsequent image processing including automatic binning and generation of cluster maps. StEMM was developed within a cardiac context and validated using syngeneic mesenchymal progenitor cells. However, this model is not restricted with regard to species or organs.
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| 26. |
- Rabitsch, Alexander, et al.
(author)
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Utilizing Multi-Connectivity to Reduce Latency and Enhance Availability for Vehicle to Infrastructure Communication
- 2022
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In: IEEE Transactions on Mobile Computing. - : Institute of Electrical and Electronics Engineers (IEEE). - 1536-1233 .- 1558-0660. ; 21:5, s. 1874-1891
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Journal article (peer-reviewed)abstract
- Cooperative Intelligent Transport Systems (C-ITS) enable information to be shared wirelessly between vehicles and infrastructure in order to improve transport safety and efficiency. Delivering C-ITS services using existing cellular networks offers both financial and technological advantages, not least since these networks already offer many of the features needed by C-ITS, and since many vehicles on our roads are already connected to cellular networks. Still, C-ITS pose stringent requirements in terms of availability and latency on the underlying communication system; requirements that will be hard to meet for currently deployed 3G, LTE, and early-generation 5G systems. Through a series of experiments in the MONROE testbed (a cross-national, mobile broadband testbed), the present study demonstrates how cellular multi-access selection algorithms can provide close to 100% availability, and significantly reduce C-ITS transaction times. The study also proposes and evaluates a number of low-complexity, low-overhead single-access selection algorithms, and shows that it is possible to design such solutions so that they offer transaction times and availability levels that rival those of multi-access solutions.
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| 27. |
- Rossi, Fiorella, et al.
(author)
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Differences and similarities between cancer and somatic stem cells : therapeutic implications
- 2020
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In: Stem Cell Research & Therapy. - : BMC. - 1757-6512. ; 11:1
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Research review (peer-reviewed)abstract
- Over the last decades, the cancer survival rate has increased due to personalized therapies, the discovery of targeted therapeutics and novel biological agents, and the application of palliative treatments. Despite these advances, tumor resistance to chemotherapy and radiation and rapid progression to metastatic disease are still seen in many patients. Evidence has shown that cancer stem cells (CSCs), a sub-population of cells that share many common characteristics with somatic stem cells (SSCs), contribute to this therapeutic failure. The most critical properties of CSCs are their self-renewal ability and their capacity for differentiation into heterogeneous populations of cancer cells. Although CSCs only constitute a low percentage of the total tumor mass, these cells can regrow the tumor mass on their own. Initially identified in leukemia, CSCs have subsequently been found in cancers of the breast, the colon, the pancreas, and the brain. Common genetic and phenotypic features found in both SSCs and CSCs, including upregulated signaling pathways such as Notch, Wnt, Hedgehog, and TGF-beta. These pathways play fundamental roles in the development as well as in the control of cell survival and cell fate and are relevant to therapeutic targeting of CSCs. The differences in the expression of membrane proteins and exosome-delivered microRNAs between SSCs and CSCs are also important to specifically target the stem cells of the cancer. Further research efforts should be directed toward elucidation of the fundamental differences between SSCs and CSCs to improve existing therapies and generate new clinically relevant cancer treatments.
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| 28. |
- Sabatier, Pierre, et al.
(author)
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An integrative proteomics method identifies a regulator of translation during stem cell maintenance and differentiation
- 2021
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 12
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Journal article (peer-reviewed)abstract
- To characterize molecular changes during cell type transitions, the authors develop a method to simultaneously measure protein expression and thermal stability changes. They apply this approach to study differences between human pluripotent stem cells, their progenies, parental and allogeneic cells. Detailed characterization of cell type transitions is essential for cell biology in general and particularly for the development of stem cell-based therapies in regenerative medicine. To systematically study such transitions, we introduce a method that simultaneously measures protein expression and thermal stability changes in cells and provide the web-based visualization tool ProteoTracker. We apply our method to study differences between human pluripotent stem cells and several cell types including their parental cell line and differentiated progeny. We detect alterations of protein properties in numerous cellular pathways and components including ribosome biogenesis and demonstrate that modulation of ribosome maturation through SBDS protein can be helpful for manipulating cell stemness in vitro. Using our integrative proteomics approach and the web-based tool, we uncover a molecular basis for the uncoupling of robust transcription from parsimonious translation in stem cells and propose a method for maintaining pluripotency in vitro.
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| 29. |
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| 30. |
- Thorén, Emma, et al.
(author)
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Compared with matched controls, patients with postoperative atrial fibrillation (POAF) have increased long-term AF after CABG, and POAF is further associated with increased ischemic stroke, heart failure and mortality even after adjustment for AF.
- 2020
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In: Clinical Research in Cardiology. - : Springer Science and Business Media LLC. - 1861-0684 .- 1861-0692. ; 109:10, s. 1232-1242
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To analyze (1) associations between postoperative atrial fibrillation (POAF) after CABG and long-term cardiovascular outcome, (2) whether associations were influenced by AF during follow-up, and (3) if morbidities associated with POAF contribute to mortality.METHODS: An observational cohort study of 7145 in-hospital survivors after isolated CABG (1996-2012), with preoperative sinus rhythm and without AF history. Incidence of AF was compared with matched controls. Time-updated covariates were used to adjust for POAF-related morbidities during follow-up, including AF.RESULTS: Thirty-one percent of patients developed POAF. Median follow-up was 9.8 years. POAF patients had increased AF compared with matched controls (HR 3.03; 95% CI 2.66-3.49), while AF occurrence in non-POAF patients was similar to controls (1.00; 0.89-1.13). The observed AF increase among POAF patients compared with controls persisted over time (> 10 years 2.73; 2.13-3.51). Conversely, the non-POAF cohort showed no AF increase beyond the first postoperative year. Further, POAF was associated with long-term AF (adjusted HR 3.20; 95% CI 2.73-3.76), ischemic stroke (1.23; 1.06-1.42), heart failure (1.44; 1.27-1.63), overall mortality (1.21; 1.11-1.32), cardiac mortality (1.35; 1.18-1.54), and cerebrovascular mortality (1.54; 1.17-2.02). These associations remained after adjustment for AF during follow-up. Adjustment for other POAF-associated morbidities weakened the association between POAF and overall mortality, which became non-significant.CONCLUSIONS: Patients with POAF after CABG had three times the incidence of long-term AF compared with both non-POAF patients and matched controls. POAF was associated with long-term ischemic stroke, heart failure, and corresponding mortality even after adjustment for AF during follow-up. The increased overall mortality was partly explained by morbidities associated with POAF.
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| 31. |
- Wedin, Johan O, et al.
(author)
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Patients With Bicuspid Aortic Stenosis Demonstrate Adverse Left Ventricular Remodeling and Impaired Cardiac Function Before Surgery With Increased Risk of Postoperative Heart Failure
- 2022
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In: Circulation. - : Lippincott Williams & Wilkins. - 0009-7322 .- 1524-4539. ; 146:17, s. 1310-1322
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Journal article (peer-reviewed)abstract
- Background: Differences in adverse cardiac remodeling between patients who have bicuspid (BAV) and tricuspid aortic valve (TAV) with severe isolated aortic stenosis (AS) and its prognostic impact after surgical aortic valve replacement remains unclear. We sought to investigate differences in preoperative diastolic and systolic function in patients with BAV and TAV who have severe isolated AS and the incidence of postoperative heart failure hospitalization and mortality. Methods: Two hundred seventy-one patients with BAV (n=152) or TAV (n=119) and severe isolated AS without coronary artery disease or other valvular heart disease, scheduled for surgical aortic valve replacement, were prospectively included. Comprehensive preoperative echocardiographic assessment of left ventricular (LV) diastolic and systolic function was performed. The heart failure events were registered during a mean prospective follow-up of 1260 days versus 1441 days for patients with BAV or TAV, respectively. Results: Patients with BAV had a more pronounced LV hypertrophy with significantly higher indexed LV mass ([LVMi] 134 g/m(2) versus 104 g/m(2), P<0.001), higher prevalence of LV diastolic dysfunction (72% versus 44%, P<0.001), reduced LV ejection fraction (55% versus 60%, P<0.001), significantly impaired global longitudinal strain (P<0.001), significantly higher NT-proBNP (N-terminal pro-brain natriuretic peptide) levels (P=0.007), and a higher prevalence of preoperative levosimendan treatment (P<0.001) than patients with TAV. LVMi was associated with diastolic dysfunction in both patients with BAV and TAV. There was a significant interaction between aortic valve morphology and LVMi on LV ejection fraction, which indicated a pronounced association between LVMi and LV ejection fraction for patients with BAV and lack of association between LVMi and LV ejection fraction for patients with TAV. Postoperatively, the patients with BAV required significantly more inotropic support (P<0.001). The patients with BAV had a higher cumulative incidence of postoperative heart failure admissions compared with patients with TAV (28.2% versus 10.6% at 6 years after aortic valve replacement, log-rank P=0.004). Survival was not different between patients with BAV and TAV (log-rank P=0.165). Conclusions: Although they were significantly younger, patients with BAV who had isolated severe AS had worse preoperative LV function and an increased risk of postoperative heart failure hospitalization compared with patients who had TAV. Our findings suggest that patients who have BAV with AS might benefit from closer surveillance and possibly earlier intervention.
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| 32. |
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