Human Heart Valves Research Articles

Prothymosin Alpha: A Novel Contributor to Estradiol Receptor Alpha-Mediated CD8+ T-Cell Pathogenic Responses and Recognition of Type 1 Collagen in Rheumatic Heart Valve Disease.

Rheumatic heart valve disease (RHVD) is a leading cause of cardiovascular death in low- and middle-income countries and affects predominantly women. The underlying mechanisms of chronic valvular damage remain unexplored and regulators of sex predisposition are unknown. Proteomics analysis of human heart valves (nondiseased aortic valves, nondiseased mitral valves [NDMVs], valves from patients with rheumatic aortic valve disease, and valves from patients with rheumatic mitral valve disease; n=30) followed by system biology analysis identified ProTα (prothymosin alpha) as a protein associated with RHVD. Histology, multiparameter flow cytometry, and enzyme-linked immunosorbent assay confirmed the expression of ProTα. In vitro experiments using peripheral mononuclear cells and valvular interstitial cells were performed using multiparameter flow cytometry and quantitative polymerase chain reaction. In silico analysis of the RHVD and Streptococcuspyogenes proteomes were used to identify mimic epitopes. A comparison of NDMV and nondiseased aortic valve proteomes established the baseline differences between nondiseased aortic and mitral valves. Thirteen unique proteins were enriched in NDMVs. Comparison of NDMVs versus valves from patients with rheumatic mitral valve disease and nondiseased aortic valves versus valves from patients with rheumatic aortic valve disease identified 213 proteins enriched in rheumatic valves. The expression of the 13 NDMV-enriched proteins was evaluated across the 213 proteins enriched in diseased valves, resulting in the discovery of ProTα common to valves from patients with rheumatic mitral valve disease and valves from patients with rheumatic aortic valve disease. ProTα plasma levels were significantly higher in patients with RHVD than in healthy individuals. Immunoreactive ProTα colocalized with CD8+ T cells in RHVD. Expression of ProTα and estrogen receptor alpha correlated strongly in circulating CD8+ T cells from patients with RHVD. Recombinant ProTα induced expression of the lytic proteins perforin and granzyme B by CD8+ T cells as well as higher estrogen receptor alpha expression. In addition, recombinant ProTα increased human leukocyte antigen class I levels in valvular interstitial cells. Treatment of CD8+ T cells with specific estrogen receptor alpha antagonist reduced the cytotoxic potential promoted by ProTα. In silico analysis of RHVD and Spyogenes proteomes revealed molecular mimicry between human type 1 collagen epitope and bacterial collagen-like protein, which induced CD8+ T-cell activation in vitro. ProTα-dependent CD8+ T-cell cytotoxicity was associated with estrogen receptor alpha activity, implicating ProTα as a potential regulator of sex predisposition in RHVD. ProTα facilitated recognition of type 1 collagen mimic epitopes by CD8+ T cells, suggesting mechanisms provoking autoimmunity.

動脈弁の弁葉に与えた構造的工夫が弁機能におよぼす影響

Recently novel artificial heart valves, which are made by using tissue regeneration techniques or the latest biocompatible materials, are actively developing. The purpose of this study is to clarify the effects of mechanical anisotropy of valve leaflet on valve functions because the new materials and human native heart valves are anisotropic. We fabricated the human aortic valve model made of polyurethane with mechanical anisotropy in valve leaflet by adding spatially periodical surface asperities. Furthermore, to determine the optimal anisotropic property of the valve leaflet, the amount of sheet thickness and the spacing of surface asperities were varied as experimental parameters. Using our fabricated in-vitro simulator, experiments were conducted under the physiological conditions of healthy adults to compare valve function between isotropic and anisotropic models. The valve function was evaluated on basis of the ISO 5840-1 and ISO 5840-2 international standards for artificial valves. The obtained results indicate that anisotropic models with 3 mm spacing were found to have the best valve function, and isotropic models and anisotropic models with 1 mm spacing were found to have similar performance. Furthermore, comparison with data from clinically used prosthetic valves showed that among anisotropic models with 3 mm spacing, the valve leaflet thickness of 280 μm was superior in both opening and closing performance.

Quantification of cell oxygenation in 2D constructs of metallized electrospun polycaprolactone fibers encapsulating human valvular interstitial cells

The present study brings developments in the area of tissue engineering of heart valves, with the design and application of a new 2D model for human heart valve. This model contains valvular interstitial cells (VIC) encapsulated in gold covered electrospun polycaprolactone (PCL/Au) fibers, the latter serving also as an electrochemical sensor that enables the monitoring of oxygen levels of cellular media. The biocompatibility of PCL and PCL/Au with VIC was evaluated after the encapsulation of VIC in both scaffolds using the lactate dehydrogenase assay. Fluorescence microscopy of the encapsulated cells was used for the investigation of cell morphology, by employing phalloidin labelled F-actin (red) and DAPI nuclear staining (blue). The electrochemical techniques allowed to investigate the effect of cell encapsulation within the PCL/Au 2D constructs and to quantify the dissolved oxygen levels in cell culture media at both PCL/Au and PCL/Au with encapsulated cells (PCL/Au/cells). Experiments were performed in a hypoxistation, which allowed a fine control on the cellular media oxygenation. Electrochemical impedance spectroscopy (EIS) was used to evaluate the electrochemical behavior of the 2D constructs, PCL/Au and PCL/Au/cells, in cellular media at different O2 concentration. Results were analyzed and both impedance values at a fixed frequency and values of the equivalent circuit elements were used to construct calibration curves for dissolved O2 determination. The second electrochemical technique used to monitor the levels of O2 at PCL/Au and PCL/Au/cells in the cellular media was square wave voltammetry with sensitivities of 1.5 and 2.5 μA cm−2 μM−1, for PCL/Au and PCL/Au/cells, respectively.

Abstract 10612: Immune Cells in Calcific Aortic Valve Disease

Introduction: Calcific aortic valve disease is a multifaceted disease in which pathogenic mineralisation of the valvular tissue occurs in tandem with fibrocalcific remodelling of the aortic valve, resulting in a wide variety of clinical presentations. Immunity, both innate and adaptive have been shown to play important roles in chronic cardiovascular diseases. Noteably, 15% of cells within healthy aortic valves are up to hematopoietic origin and these populations are further increased within calcified valves however, the role of the immune system within CAVD remains to be elucidated. Objectives: Investigate the prevalence and distribution of immune cells within CAVD. Methods & Results: Human calcified aortic heart valves were obtained from valve replacement surgeries. Immunohistological assessment of immune cells within the tissue was conducted, with the presence of T cells, B cells, macrophages and dendritic cells detected in the vicinity of calcific nodules. Flow cytometry analysis of cells isolated from the valve was conducted. 69% of cells isolated from the valve were CD45+, with 57% and 42% of CD45+ CD3+ presenting as CD8+ and CD4+ respectively. Within the CD8+ population, 56% of these were central memory CD8+ T cells, with 24% as activated CD8+ T cells. Likewise, within the CD4+ population 29.5% CD4+ cells were activated T cells and 55% central memory T cells. Small populations of naïve CD4+ and CD8+ T cells; 9% and 13% respectively, were present within the valve. CD45+, CD3+, CD4+/CD8+ cells were isolated via FACS and their global proteomic profile was analysed on the Thermo Scientific Lumos orbitrap mass spectrometer. IL-31RA was present within the T cell population, alongside MAPK pathway mediators were also present. Network analysis of T cell proteomics showed increased IL-4 and IL-13 pathways (p<0.01) indicative of a Type II inflammatory pathway, correlating with the presence of basophils and eosinophils present within the valve. Conclusions: Prevalence of immune cells within the valve suggests an inflammatory role in the development of calcific aortic valve disease, with the prevalence of T cells within the valve suggesting an adaptive immune response may be central to the pathology of CAVD.

Importance of Non-Newtonian Modeling of Blood Flow for Calcified Aortic Valves: Relevance to Sub-Clinical Thrombosis

Objective: The Newtonian assumption for blood has often been applied for aortic valve studies where high shear rates can be seen on the ventricularis side. However, in the presence of calcifications this assumption is suspect due to large flow disturbances, especially on the fibrosa side. Regions of low wall shear stress (WSS) have been known to lead to thrombogenesis in the cardiovascular system, and thus accurate blood flow modeling is required to predict these locations. This study looked at the applicability of a Newtonian and non-Newtonian, Carreau, model for blood on a healthy and calcified aortic valve geometry. Methods: A reconstructed human aortic heart valve from an 82-year old patient at the early diastolic phase was commercially acquired (Valve - 012 - Heart Print catalog, Materialize Inc., Plymouth MI). Inlet velocity of 1 cm/s was prescribed and an 80-mmHg pressure condition for the outlet boundary condition. Fluent (ANSYS Inc, Canonsburg, PA) was used for solving the unsteady Navier-Stokes equations. Combinations of a healthy or calcified valve and a Newtonian or a non-Newtonian model were then simulated. Results: WSS showed little difference between Newtonian and non-Newtonian models in the healthy valve (Figure 1A and Figure 1B). However, there was an underestimation of WSS in the calcified case using the Newtonian model compared to non-Newtonian (Figure 1C and Figure 1D) in certain core leaflet regions. Conclusions: The Newtonian assumption can be used for modeling blood flow of a healthy aortic valve, but a non-Newtonian model must be used in cases of valve disease, such as severely calcified aortic valves. These irregularities affect determining WSS where a few dynes/cm2 mark the difference between regions being susceptible to potential thrombus or not. Figure 1. Results on the fibrosa side of the aortic valve A) WSS using a Newtonian model on a healthy valve. B) WSS using a non-Newtonian, Carreau, model on a healthy valve. C) WSS using a Newtonian model on calcified valve. D) WSS using a non-Newtonian, Carreau, model on a calcified valve

Fabricating hydrogels to mimic biological tissues of complex shapes and high fatigue resistance

<h2>Summary</h2> Biological tissues, such as heart valves and vocal cords, function through complex shapes and high fatigue resistance. Achieving both attributes with synthetic materials is hitherto an unmet challenge. Here we meet this challenge with hydrogels of heterogeneous structures. We fabricate a three-dimensional hydrogel skeleton by stereolithography and a hydrogel matrix by cast. Both the skeleton and matrix are elastic and stretchable, but the skeleton is much stiffer than the matrix, and their polymer networks entangle topologically. When such a hydrogel is stretched, the compliance of the matrix deconcentrates stress in the skeleton and amplifies fatigue resistance. We fabricate a homogeneous hydrogel and a heterogeneous hydrogel, each in the shape of a human heart valve. Subject to cyclic pressure, the former fractures in ∼560 cycles but the latter is intact after 50,000 cycles. Soft materials of complex shapes and high fatigue resistance open broad opportunities for applications.

Transplantation of cryopreserved human heart valves in Europe: 30years of banking in Brussels and future perspectives.

For over 30 years, our TE has processed, controlled for quality and distributed cryopreserved allograft valves for human application. We present a review of this activity and future perspectives of cardiovascular tissue banking. The donor age and medical/behavioral history are in compliance with the regulations of the EUMS. Allograft morphology and function are evaluated in a class A cleanroom. Tests for viral/bacterial infection, histological control of structure/infection/malignancy and control-rate cryopreservation are performed. A total of 7562 hearts were sent to our TE, whereas 7290 valves (pulmonary, aortic and mitral) were transplanted. The donations increased over time: 1934, 2566 and 3062 hearts were donated during the first, second and third decades (increases of 32.7 and 19.3% during the second and third decades). Likewise, there was a significant increase in transplantations with 2050, 2550 and 2690 valves implanted during the first, second and third decades (24.4 and 5.5% increase during the second and third decades). A total of 4475 pulmonary (61.4%), 2760 aortic (37.9%) and 55 mitral valves (0.7%) were transplanted. Outstanding long-term results in adults and evidence of immune-related deterioration of allografts in neonates and infants were demonstrated. Decellularization was suggested as a solution. One hundred pulmonary and 180 aortic valves were sent for transplantation after decellularization for the ESPOIR and ARISE clinical trials and beyond. The donation and transplantation activity increased progressively. Although cryopreserved valves represent the best substitute for diseased valves, accelerated failure appears after implantation in neonates and infants. The implementation of new technologies, such as decellularization, as a standard procedure for treatment of allograft valves will offer further improvements in allograft quality and increase of durability.

Crosslinking porcine aortic valve by radical polymerization for the preparation of BHVs with improved cytocompatibility, mild immune response, and reduced calcification.

Over one million artificial heart valve transplantations are performed each year due to valvular stenosis or regurgitation. Among them, bioprosthetic heart valves (BHVs) are increasingly being used because of the absence of the need for lifelong anticoagulation. Almost all of the commercial BHVs are treated with Glutaraldehyde (GLUT). As GLUT-treated BHVs are prone to calcification and structural degradation, their durability is greatly reduced with a service life of only 12-15 years. The physiological structure and mechanical properties of the porcine aortic valve (PAV) are closer to that of a human heart valve, so in this study, PAV is used as the model to explore the comprehensive properties of the prepared BHVs by radical polymerization crosslinking method. We found that PAV treated by radical polymerization crosslinking method showed similar ECM stability and biaxial mechanical properties with GLUT-treated PAV. However, radical polymerization crosslinked PAV exhibited better cytocompatibility and endothelialization potential in vitro cell experiment as better anticalcification potential and reduced immune response than GLUT-treated PAV through subcutaneous animal experiments in rats. To conclude, a novel crosslinking method of non-glutaraldehyde fixation of xenogeneic tissues for the preparation of BHVs is expected.

A bioprosthetic heart valve cross-linked by a non-glutaraldehyde reagent with improved biocompatibility, endothelialization, anti-coagulation and anti-calcification properties.

Valvular heart disease is an important disease that endangers human health and heart valve replacement has become one of the main treatments for patients with severe valvular heart disease. However, the traditional surgical valve replacement (SVR) suffers several drawbacks such as high risk, great trauma and long recovery time, and more than 30% of patients are intolerant to SVR, especially elderly patients. In recent years, with the development of minimally invasive technology, transcatheter heart valve replacement (THVR) as a method of implantation without thoracotomy has become an optimal treatment for severe valvular heart disease due to its advantages of minimal trauma, low risk and fast recovery. Meanwhile, the usage of bioprosthetic heart valves (BHVs) has been enlarged greatly with the rapid development of THVR and the aging population. Most BHVs in clinics are crosslinked by glutaraldehyde (Glut), which shows great mechanical properties and chemical stability. However, some problems such as poor biocompatibility, calcification, coagulation and endothelialization difficulty also need to be solved urgently for Glut-treated BHVs. In this work, a non-Glut treated BHV from 7a-ethyltetrahydro-oxazolo[3,4-c]oxazole (OX-Et) crosslinked porcine pericardium (PP) has been developed. Compared with glutaraldehyde-crosslinked porcine pericardium (Glut-PP), good physical and chemical properties similar to Glut-PP are shown for OX-Et treated porcine pericardium (OX-Et-PP). It is noteworthy that better biocompatibility, endothelialization performance, and anti-coagulant effect as well as the improved anti-calcification property can also be observed for OX-Et-PP in the in vitro and in vivo study, potentially making OX-Et-PP a good candidate in the application of BHVs.

Abstract 13401: Prothymosin Alpha (Protα) Associates With Pathogenesis and Sex Predisposition in Rheumatic Heart Valve Disease

Introduction: Acute rheumatic fever (ARF) results from autoimmune responses to group A streptococcus. ARF can cause chronic rheumatic heart valve disease (RHVD), a major public health burden in low- and middle-income countries. Although ARF affects both sexes equally, females have a higher prevalence of RHVD. We identified a target protein, ProTα, that may contribute to pathophysiology of and gender predisposition in RHVD. Estradiol regulates ProTα, which influences transcriptional activity of the estrogen receptor (ER). Methods: Human heart valves (n=120) obtained from heart transplantation and valve replacement surgeries, including non-diseased mitral and aortic valves (NDMV and NDAV, n=17/group), rheumatic mitral and aortic valves (RMVD, n=45; RAVD, n=8) and calcifying valves from patients with calcific aortic valve disease (CAVD, n=33) underwent proteomic and network analyses, and immunohistochemical assessment of CD68, CD4, CD8 and ProTα. ProTα levels were measured in plasma and peripheral mononuclear cells (PBMCs) from RHVD patients and healthy donors (n=14/group) by ELISA and flow cytometry. Results: A comparison of proteomes from NDMV and NDAV established the baseline differences between valve types. 12 proteins were enriched (q&lt;0.05) in NDMV that may indicate the mitral valve predisposition to RVHD. Proteome analysis of non-diseased and diseased valves (NDMV vs RMVD, NDAV vs RAVD) identified a total of 213 proteins enriched in RHVD (q&lt;0.05). The expression of the 12 NDMV-enriched proteins were evaluated across the 213 proteins enriched in diseased valves, resulting in the identification of ProTα common to both the RMVD and RAVD proteomes, but absent in CAVD. Additional KEGG pathway enrichment analyses linked 6 among 213 proteins with the estrogen signaling pathway (p&lt;0.05). Immunoreactive ProTα colocalized with T CD8 cells in RHVD. ProTα and ERα also correlated strongly in circulating T CD8 cells in RHVD (p&lt;0.05). ProTα plasma levels were higher in RHVD patients than healthy individuals (2 fold, p&lt;0.05). Conclusion: We propose that ProTα is a novel contributor to the immunopathogenesis of RHVD and may regulate sex predisposition in this disease.

Histological assessment of the human heart valves and its relationship with age.

The human heart valves are complex anatomical structures consisting of leaflets with many supporting structures. With advancing age, the microstructure of the components of the valves can change. Knowledge and understanding of the anatomical relationships between the different components of the heart valve structures and their relationship with age is crucial for the development and progression of treatment of valvular disease. The purpose of this study was to determine histological changes of the components of the heart valves and their relationship with age. Fifty hearts taken from cadavers were included to examine the histology of the tricuspid, mitral, pulmonary, and aortic valves. All specimens were stained with Elastic Van Gieson, and picrosirius red to enable the evaluation of elastic and collagen fibers, respectively. There was a gradual increase in elastic and collagen fibers with advancing age, particularly over 40 years, in all valve types. In the case of tricuspid and mitral valves increases in collagen and elastic fibers were observed starting in the fifth decade. Elastic fiber fragmentation was observed in specimens over 50 years. In the case of the pulmonary and the aortic valves, collagen fibers were denser and more irregular in the sixth to seventh decades when compared to younger ages while elastic fibers were significantly increased in the sixth decade. In addition, an increase in fat deposition had an association with aging. These findings provide additional basic knowledge in age-related morphological changes of the heart valves and will increase understanding concerning valvular heart diseases and treatment options.

Bacterial biofilms in infective endocarditis: an in vitro model to investigate emerging technologies of antimicrobial cardiovascular device coatings

ObjectiveIn spite of the progress in antimicrobial and surgical therapy, infective endocarditis (IE) is still associated with a high morbidity and mortality. IE is characterized by bacterial biofilms of the endocardium, especially of the aortic and mitral valve leading to their destruction. About one quarter of patients with formal surgery indication cannot undergo surgery. This group of patients needs further options of therapy, but due to a lack of models for IE prospects of research are low. Therefore, the purpose of this project was to establish an in vitro model of infective endocarditis to allow growth of bacterial biofilms on porcine aortic valves, serving as baseline for further research.Methods and resultsA pulsatile two-chamber circulation model was constructed that kept native porcine aortic valves under sterile, physiologic hemodynamic and temperature conditions. To create biofilms on porcine aortic valves the system was inoculated with Staphylococcus epidermidis PIA 8400. Aortic roots were incubated in the model for increasing periods of time (24 h and 40 h) and bacterial titration (1.5 × 104 CFU/mL and 1.5 × 105 CFU/mL) with 5 L cardiac output per minute. After incubation, tissue sections were analysed by fluorescence in situ hybridization (FISH) for direct visualization of the biofilms. Pilot tests for biofilm growth showed monospecies colonization consisting of cocci with time- and inocula-dependent increase after 24 h and 40 h (n = 4). In n = 3 experiments for 24 h, with the same inocula, FISH visualized biofilms with ribosome-containing, and thus metabolic active cocci, tissue infiltration and similar colonization pattern as observed by the FISH in human IE heart valves infected by S. epidermidis.ConclusionThese results demonstrate the establishment of a novel in vitro model for bacterial biofilm growth on porcine aortic roots mimicking IE. The model will allow to identify predilection sites of valves for bacterial adhesion and biofilm growth and it may serve as baseline for further research on IE therapy and prevention, e.g. the development of antimicrobial transcatheter approaches to IE.Graphic abstract

A Proof of Concept Study of Using Machine-Learning in Artificial Aortic Valve Design: From Leaflet Design to Stress Analysis.

Artificial heart valves, used to replace diseased human heart valves, are life-saving medical devices. Currently, at the device development stage, new artificial valves are primarily assessed through time-consuming and expensive benchtop tests or animal implantation studies. Computational stress analysis using the finite element (FE) method presents an attractive alternative to physical testing. However, FE computational analysis requires a complex process of numeric modeling and simulation, as well as in-depth engineering expertise. In this proof of concept study, our objective was to develop machine learning (ML) techniques that can estimate the stress and deformation of a transcatheter aortic valve (TAV) from a given set of TAV leaflet design parameters. Two deep neural networks were developed and compared: the autoencoder-based ML-models and the direct ML-models. The ML-models were evaluated through Monte Carlo cross validation. From the results, both proposed deep neural networks could accurately estimate the deformed geometry of the TAV leaflets and the associated stress distributions within a second, with the direct ML-models (ML-model-d) having slightly larger errors. In conclusion, although this is a proof-of-concept study, the proposed ML approaches have demonstrated great potential to serve as a fast and reliable tool for future TAV design.

Decellularized pig pulmonary heart valves-Depletion of nucleic acids measured by proviral PERV pol.

Decellularized human pulmonary heart valve (dhHV) scaffolds have been shown to be the gold standard especially for younger, adolescent patients. However, human heart valves are limited in availability. Xenogeneic decellularized pig heart valves (dpHV) may serve as alternative. The efficacy of DNA reduction processes upon decellularization of heart valves from German Landrace pigs was analyzed by measurements of remaining nucleic acids including proviral porcine endogenous retrovirus (PERV) sequences. Porcine pulmonary heart valves (pPHV) were decellularized by three different protocols and further treated with DNaseI or Benzonase, at varying incubation times. DNA isolated from valve associated muscle (m), valve cusp (c), and pulmonary artery (pa) was monitored by PCR and qRT-PCR using GAPDH and the PERV polymerase (pol) for read-out. Decellularization of pPHV led to a significant reduction of DNA (>99%) which could be further significantly increased for (m) and (pa) by nuclease treatment, reducing proviral PERV pol from approximately 5×107 to 5×103 copies/mg in nuclease treated tissues. Both nucleases demonstrated comparable activities. But DNaseI revealed to be less consistent for PERV, especially at muscular tissue. Noteworthy, remaining proviral sequences are still detectable by PCR; however, due to the absence of the cellular replication machinery the production of infectious particles is not expected. Decellularization and nuclease treatment of pPHV is an efficient procedure to reduce the DNA content including PERV, thus represents a valuable option to increase virus safety independently from the source animal background.

Molecular typing of Coxiella burnetii from sheep in Egypt

Coxiella burnetii, the etiological agent of Q fever, is a globally distributed zoonotic disease. The disease was reported serologically in different animal species and humans in Egypt but the genetic information about circulating Coxiella strains is limited. The present study aimed to genetically characterize Coxiella positive samples, identified in abortive sheep, based on a 17-loci Multiple Locus Variable number tandem repeat analysis (MLVA) panel and Multispacer Sequence Typing (MST). Four MLVA types were found among six examined samples. While all three samples examined by MST were identified as novel sequence type (ST) closely related to human heart valve isolates from France, Saudi Arabia, USA and United Kingdom. This study provides the first genetic information about circulating Coxiella strains in Egypt and improves epidemiological data of Q fever in the country.

Human cell-derived tissue-engineered heart valve with integrated Valsalva sinuses: towards native-like transcatheter pulmonary valve replacements

Transcatheter valve replacement indication is currently being extended to younger and lower-risk patients. However, transcatheter prostheses are still based on glutaraldehyde-fixed xenogeneic materials. Hence, they are prone to calcification and long-term structural degeneration, which are particularly accelerated in younger patients. Tissue-engineered heart valves based on decellularized in vitro grown tissue-engineered matrices (TEM) have been suggested as a valid alternative to currently used bioprostheses, showing good performance and remodeling capacity as transcatheter pulmonary valve replacement (TPVR) in sheep. Here, we first describe the in vitro development of human cell-derived TEM (hTEM) and their application as tissue-engineered sinus valves (hTESVs), endowed with Valsalva sinuses for TPVR. The hTEM and hTESVs were systematically characterized in vitro by histology, immunofluorescence, and biochemical analyses, before they were evaluated in a pulse duplicator system under physiological pulmonary pressure conditions. Thereafter, transapical delivery of hTESVs was tested for feasibility and safety in a translational sheep model, achieving good valve performance and early cellular infiltration. This study demonstrates the principal feasibility of clinically relevant hTEM to manufacture hTESVs for TPVR.

Vascular endothelial growth factor-loaded elastin-hydrogel modification of the pericardium improves endothelialization potential of bioprosthetic heart valves.

Glutaraldehyde-fixed pericardium is widely used to replace human heart valves. The lack of endothelialization contributes to calcification and structural-valve deterioration, which is particularly ...

Fixed Points and Stability Analysis in the Motion of Human Heart Valve Leaflet

This work was set out to gain further insight into the kinetics of the human heart valve leaflet. The Korakianitis and Shi lumped parameter model was adopted for this study. The fixed points were determined, and then, their stability properties were assessed by evaluating eigenvalues of the Jacobian matrices. Normal physiological parameters for the valve model were simulated; based on which, a local bifurcation diagram was generated. Phase portraits were plotted from simulated responses, and were used to observe the qualitative properties of the valve leaflet motion. The evaluated fixed points were found to be dependent on pressure and flow effects, and independent on friction or damping effect. Observed switching of stability between the two fixed points indicated that the leaflet motion undergoes transcritical bifurcation. Of the two fixed points, one is always either a stable spiral or generative node while the other is a saddle. Numerical simulations were carried out to verify the analytical solutions.

Coupled OPG-Fc on Decellularized Aortic Valves by EDC/NHS Attenuates Rat MSCs Calcification In Vitro.

Valve calcification commonly damages natural human heart valves and tissue-engineered heart valves (TEHVs), and no ideal intervention is available in clinical practice. It is increasingly considered that osteoprotegerin (OPG) inhibits vascular calcification. Herein we aimed to explore whether free OPG-Fc fusion protein or coupled OPG-Fc on decellularized aortic valves attenuates calcification. Calcification of rat bone marrow-derived mesenchymal stromal cells (MSCs) was induced by osteogenic differentiation media, and the effects of free OPG-Fc or OPG-Fc coupled on the decellularized porcine aortic heart valve leaflet scaffolds by coupling agents 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC)/N-hydroxysuccinimide (NHS) on calcification were observed. Mineralization of the extracellular matrix, alkaline phosphatase (ALP) activity, and expression of osteoblastic markers were assessed to determine the calcification kinetics. Our results indicated that the matrix calcium content and the ALP activity, as well as the mRNA expression levels of a bone morphogenetic protein-2 (BMP-2), osteopontin (OPN), and osteocalcin (OC), of the MSCs seeded on plates with free OPG-Fc or on the OPG-Fc-coupled scaffolds decreased compared with their control MSCs without coupled OPG-Fc. The results suggest that both free and immobilized OPG-Fc on the decellularized aortic valve scaffolds by EDC/NHS can attenuate the calcification of MSCs induced by osteogenic differentiation media, implying that OPG-Fc might be a new treatment or prevention strategy for the calcification of natural human heart valves and TEHVs in the future.

Gross age-related changes and diseases in human heart valves.

Cardiac valves are highly complex structures optimizing their function during the cardiac cycle. They open and close directed by blood flow under different pressure conditions in the dynamic environment in the heart. It is acknowledged that the aging process affects the structure and functions of the heart valves. With regard to morphometry, age-related changes of the heart valve can be found in valve circumference, thickness of the leaflet, luminal area at the sinotubular junction, valve diameter, orifice area, and leaflet size in circumferential and radial direction. In addition, there are differences between male and female hearts in some features. Moreover, there are studies the qualitative and quantitative assessment of histological compositions, echocardiography study to investigate the annular circumference and diameter in the human heart valves related with age. Studies into the detailed anatomy of the changes in heart valves with age are important and the correlation between valve morphology and age may be used as an age indicator. This study reviews the basic anatomical structure of the heart valves, age-related changes of valve morphometry, heart valve diseases, and general treatment of valvular diseases in humans. Detailed knowledge of the anatomical features of the morphology of the human heart valve is useful for any treatments of valve pathology.