Anticoagulant therapy in pregnant women with mechanical and bioprosthetic heart valves.

OBJECTIVE: The aim of the present study was to review maternal and fetal outcomes in pregnant women with prosthetic heart valves. METHODS: A retrospective record review of pregnant women with prosthetic heart valves on anticoagulation was performed at the Specialist Cardiac Antenatal Clinic, Johannesburg South Africa from 2015 to 2023. RESULTS: Fifty pregnancies with mechanical heart valves and three with tissue valves, on anticoagulation for comorbid atrial fibrillation were identified. The majority were of African ethnicity at a mean age of 33 ± 6 years. Anti-Xa adjusted enoxaparin was commenced at 10.5 ± 5.6 weeks' gestation until delivery in 48 (90.6%) pregnancies and warfarin was continued in five (9.4%) pregnancies. The live birth rates on enoxaparin and warfarin were 56.3% (95% confidence interval [CI]: 42.3-69.3) and 20.0% (95% CI: 2.0-64.0), respectively. There were 12 (22.6%) miscarriages at a mean of 11.3 ± 3.7 weeks' gestation, four (7.5%) intrauterine fetal deaths on warfarin and two (3.8%) warfarin embryopathy/fetopathy. The rates of antepartum/secondary postpartum bleeding and primary postpartum bleeding were 29.4% (95% CI: 18.6-43.1) and 5.9% (95% CI: 1.4-16.9), respectively. Maternal complications included anemia (n = 11, 20.8%), arrhythmia (n = 2, 3.8%), heart failure (n = 2, 3.8%) and paravalvular leak (n = 2, 3.8%). There was one (1.9%) mitral valve thrombosis and one (1.9%) stuck valve in pregnancies who defaulted warfarin prior to pregnancy. There were no maternal deaths. CONCLUSION: Multidisciplinary management of pregnant women with prosthetic heart valves with anti-Xa adjusted low molecular weight heparin throughout pregnancy represents an effective anticoagulation option for low-middle-income countries.

Can mechanical heart valves perform similarly to tissue valves? An in vitro study.

Current surgical aortic valve (AV) replacement options include bioprosthetic and mechanical heart valves (MHVs), each with inherent limitations. Bioprosthetic valves offer superior hemodynamics but suffer from durability issues, typically initiating deterioration within 7-8 years. MHVs, while durable, necessitate lifelong anticoagulation therapy, presenting risks such as severe bleeding and thromboembolic events. The need for anticoagulants is caused by non-physiological flow through the hinge area during the closed phase and large spikes of regional backflow velocity (RBV) during the closing phase that produces high shear events. This study introduces the iValve, a novel MHV designed to combine the hemodynamic benefits of bioprosthetic valves with the durability of MHVs without requiring anticoagulation. The iValve features eye-like leaflets, a saddle-shaped housing, and an optimized hinge design to enhance blood flow and minimize thrombotic risk. Fabricated using 6061-T6 aluminum and polyether ether ketone (PEEK), twelve iValve iterations were evaluated for their opening and closing dynamics. The reported top-performing prototypes demonstrated competitive performance against industry standards. The proposed iValve prototype exhibited a mean RBV of -4.34 m/s with no spikes in RBV, performing similarly to bioprosthetic valves and significantly outperforming existing MHVs. The iValve's optimized design showed a 7-10% reduction in closing time and a substantial decrease in RBV spikes, potentially reducing the need for anticoagulation therapy. This study highlights the iValve's potential to revolutionize prosthetic heart valve technology by offering a durable, hemodynamically superior solution that mitigates the drawbacks of current MHVs.

The α-Gal KO Mouse Animal Model is a Reliable and Predictive Tool for the Immune-Mediated Calcification Assessment of Heart Valve Bioprostheses.

BACKGROUND: Recent studies highlighted the presence of anti-α-Gal antibodies in patients implanted with commercial bioprosthetic heart valves (BHVs). BHVs expose residual α-Gal xenoantigen and their recognition by the circulating anti-Gal antibodies leads to opsonization of the device's tissue component with the consequent triggering of a deterioration pathway that culminates with calcification. Small animal models such as mice and rats have been broadly involved in the in vivo testing of biomaterials by subcutaneous implantation, especially for the effectiveness of BHVs anti-calcific treatments. However, since models employed for this purpose express α-Gal antigen, the implantation of BHVs' leaflets does not elicit a proper immunological response, so the calcification propensity may be dramatically underestimated. METHODS: An α-Gal knockout (KO) mouse model has been created, using the CRISP/Cas9 approach, and adopted to assess the calcification potential of commercial BHVs leaflets through the surgical implantation in the back subcutis area. Calcium quantification was performed by inductively coupled plasma analysis; immune response against the BHVs leaflets and α-Gal silencing was evaluated through immunological assays. RESULTS: Two months after the implantation of commercial BHV leaflets, the anti-Gal antibody titers in KO mice doubled when compared with those found in wild-type (WT) ones. Leaflets explanted from KO mice, after one month, showed a four-time increased calcium deposition concerning the ones explanted from WT. The degree of silencing of α-Gal varied, depending on the specific organ that was assessed. In any case, the animal model was suitable for evaluating implanted tissue responses. CONCLUSIONS: Such mouse model proved to be an accurate tool for the study of the calcific propensity of commercial BHVs leaflets than those hitherto used. Given its reliability, it could also be successfully used to study even other diseases in which the possible involvement of α-Gal has been observed.

A strategy for mechanically integrating robust hydrogel-tissue hybrid to promote the anti-calcification and endothelialization of bioprosthetic heart valve.

Bioprosthetic heart valve (BHV) replacement has been the predominant treatment for severe heart valve diseases over decades. Most clinically available BHVs are crosslinked by glutaraldehyde (GLUT), while the high toxicity of residual GLUT could initiate calcification, severe thrombosis, and delayed endothelialization. Here, we construed a mechanically integrating robust hydrogel-tissue hybrid to improve the performance of BHVs. In particular, recombinant humanized collagen type III (rhCOLIII), which was precisely customized with anti-coagulant and pro-endothelialization bioactivity, was first incorporated into the polyvinyl alcohol (PVA)-based hydrogel via hydrogen bond interactions. Then, tannic acid was introduced to enhance the mechanical performance of PVA-based hydrogel and interfacial bonding between the hydrogel layer and bio-derived tissue due to the strong affinity for a wide range of substrates. In vitro and in vivo experimental results confirmed that the GLUT-crosslinked BHVs modified by the robust PVA-based hydrogel embedded rhCOLIII and TA possessed long-term anti-coagulant, accelerated endothelialization, mild inflammatory response and anti-calcification properties. Therefore, our mechanically integrating robust hydrogel-tissue hybrid strategy showed the potential to enhance the service function and prolong the service life of the BHVs after implantation.

Valve-in-Valve Transcatheter Aortic Valve Replacement: From Pre-Procedural Planning to Procedural Scenarios and Possible Complications.

Over the last decades, bioprosthetic heart valves (BHV) have been increasingly implanted instead of mechanical valves in patients undergoing surgical aortic valve replacement (SAVR). Structural valve deterioration (SVD) is a common issue at follow-up and can justify the need for a reintervention. In the evolving landscape of interventional cardiology, valve-in-valve transcatheter aortic valve replacement (ViV TAVR) has emerged as a remarkable innovation to address the complex challenges of patients previously treated with SAVR and has rapidly gained prominence as a feasible technique especially in patients at high surgical risk. On the other hand, the expanding indications for TAVR in progressively younger patients with severe aortic stenosis pose the crucial question on the long-term durability of transcatheter heart valves (THVs), as patients might outlive the bioprosthetic valve. In this review, we provide an overview on the role of ViV TAVR for failed surgical and transcatheter BHVs, with a specific focus on current clinical evidence, pre-procedural planning, procedural techniques, and possible complications. The combination of integrated Heart Team discussion with interventional growth curve makes it possible to achieve best ViV TAVR results and avoid complications or put oneself ahead of time from them.

Recent progress in functional modification and crosslinking of bioprosthetic heart valves.

Valvular heart disease (VHD), clinically manifested as stenosis and regurgitation of native heart valve, is one of the most prevalent cardiovascular diseases with high mortality. Heart valve replacement surgery has been recognized as golden standard for the treatment of VHD. Owing to the clinical application of transcatheter heart valve replacement technic and the excellent hemodynamic performance of bioprosthetic heart valves (BHVs), implantation of BHVs has been increasing over recent years and gradually became the preferred choice for the treatment of VHD. However, BHVs might fail within 10-15 years due to structural valvular degeneration (SVD), which was greatly associated with drawbacks of glutaraldehyde crosslinked BHVs, including cytotoxicity, calcification, component degradation, mechanical failure, thrombosis and immune response. To prolong the service life of BHVs, much effort has been devoted to overcoming the drawbacks of BHVs and reducing the risk of SVD. In this review, we summarized and analyzed the research and progress on: (i) modification strategies based on glutaraldehyde crosslinked BHVs and (ii) nonglutaraldehyde crosslinking strategies for BHVs.

Embedding and Backscattered Scanning Electron Microscopy (EM-BSEM) Is Preferential over Immunophenotyping in Relation to Bioprosthetic Heart Valves.

Hitherto, calcified aortic valves (AVs) and failing bioprosthetic heart valves (BHVs) have been investigated by similar approaches, mostly limited to various immunostaining techniques. Having employed multiple immunostaining combinations, we demonstrated that AVs retain a well-defined cellular hierarchy even at severe stenosis, whilst BHVs were notable for the stochastic degradation of the extracellular matrix (ECM) and aggressive infiltration by ECM-digesting macrophages. Leukocytes (CD45+) comprised ≤10% cells in the AVs but were the predominant cell lineage in BHVs (≥80% cells). Albeit cells with uncertain immunophenotype were rarely encountered in the AVs (≤5% cells), they were commonly found in BHVs (≥80% cells). Whilst cell conversions in the AVs were limited to the endothelial-to-mesenchymal transition (represented by CD31+α-SMA+ cells) and the formation of endothelial-like (CD31+CD68+) cells at the AV surface, BHVs harboured numerous macrophages with a transitional phenotype, mostly CD45+CD31+, CD45+α-SMA+, and CD68+α-SMA+. In contrast to immunostaining, which was unable to predict cell function in the BHVs, our whole-specimen, nondestructive electron microscopy approach (EM-BSEM) was able to distinguish between quiescent and matrix-degrading macrophages, foam cells, and multinucleated giant cells to conduct the ultrastructural analysis of organelles and the ECM, and to preserve tissue integrity. Hence, we suggest EM-BSEM as a technique of choice for studying the cellular landscape of BHVs.

An Evidence-Based Approach to Anticoagulation Therapy Comparing Direct Oral Anticoagulants and Vitamin K Antagonists in Patients With Atrial Fibrillation and Bioprosthetic Valves: A Systematic Review, Meta-Analysis, and Network Meta-Analysis.

Direct oral anticoagulants (DOACs) are a newer class of anticoagulants that inhibit factor Xa or factor IIa and include drugs such as rivaroxaban, apixaban, edoxaban, betrixaban, and dabigatran. Although vitamin K antagonists (VKAs) have been traditionally used to prevent thromboembolic events, DOACs have gained popularity because of their faster onset and offset of action and reduced need for monitoring. This study aimed to provide more data for anticoagulants in patients with atrial fibrillation with bioprosthetic heart valves by incorporating all available trials to date. A search was performed across 5 electronic databases to identify relevant studies. We analyzed the data using a pooled risk ratio for categorical outcomes and used the I2 test to determine heterogeneity. The quality of randomized controlled trials was assessed using the Cochrane risk of bias assessment tool, and the National Institutes of Health tool was used for observational studies. Our study included a frequentist network meta-analysis (MA) of the aggregate data to obtain the network estimates for the outcomes of interest. We retrieved 28 studies with a total of 74,660 patients with bioprosthetic heart valves. Our MA significantly showed that DOACs decrease the risk of all-cause bleeding (risk ratio [RR] 0.80, 95% confidence interval [CI] 0.75 to 0.85, p >0.00001), stroke and systemic embolization (RR 0.89, 95% CI 0.80 to 0.99, p = 0.03), and intracranial bleeding outcomes (RR 0.62, 95% CI 0.45 to 0.86, p = 0.004) compared with VKA. In contrast, there was no significant difference between the compared groups in major bleeding (RR = 0.92, 95% CI 0.84 to 1.02, p = 0.10) and all-cause mortality outcomes (RR = 0.96, 95% CI 0.85 to 1.07, p = 0.43), respectively. In addition, the network MA results did not favor any of the studied interventions over each other (p <0.05) regarding all-cause bleeding, mortality, stroke and systemic embolization, and major bleeding outcomes. In conclusion, our study found that DOACs are more effective in reducing the risk of bleeding, stroke, systemic embolism, and intracranial bleeding than VKAs. However, no significant difference was observed in the incidence of gastrointestinal bleeding, major bleeding, thromboembolic events, and all-cause mortality. In addition, our network MA did not identify any specific DOAC treatment as more favorable than others.

Biomimetic-modified bioprosthetic heart valves with Cysteine-Alanine-Glycine peptide for anti-thrombotic, endothelialization and anti-calcification.

In recent years, bioprosthetic heart valves (BHVs) prepared by cross-linking porcine or bovine pericardium with glutaraldehyde (Glut) have received widespread attention due to their excellent hemocompatibility and hydrodynamic properties. However, the failure of BHVs induced by thrombosis and difficulty in endothelialization still exists in clinical practice. Improving the biocompatibility and endothelialization potential of BHVs is conducive to promoting their anti-thrombosis properties and prolonging their service life. Herein, Cysteine-Alanine-Glycine (CAG) peptide was introduced into the biomimetic BHV materials modified by 2-methacryloyloxyethyl phosphorylcholine (MPC) to improve their anti-thrombosis and promoting-endothelialization performances. MPC can improve the anti-adsorption performance of BHV materials, as well as, CAG contributes to the adhesion and proliferation of endothelial cells on the surface of BHV materials. The results of experiments showed that the biomimetic modification strategy with MPC and CAG reduce the thrombosis of BHV materials and improve their endothelialization in vitro. More importantly, the calcification of BHV significantly reduced by inhibiting the expression of M1 macrophage-related factors (IL-6, iNOS) and promoting the expression of M2 macrophage-related factors (IL-10, CD206). We believe that the valve-modified strategy is expected to provide effective solutions to clinical valve problems.

Differential Immune Response to Bioprosthetic Heart Valve Tissues in the α1,3Galactosyltransferase-Knockout Mouse Model.

Structural valve deterioration (SVD) of bioprosthetic heart valves (BHVs) has great clinical and economic consequences. Notably, immunity against BHVs plays a major role in SVD, especially when implanted in young and middle-aged patients. However, the complex pathogenesis of SVD remains to be fully characterized, and analyses of commercial BHVs in standardized-preclinical settings are needed for further advancement. Here, we studied the immune response to commercial BHV tissue of bovine, porcine, and equine origin after subcutaneous implantation into adult α1,3-galactosyltransferase-knockout (Gal KO) mice. The levels of serum anti-galactose α1,3-galactose (Gal) and -non-Gal IgM and IgG antibodies were determined up to 2 months post-implantation. Based on histological analyses, all BHV tissues studied triggered distinct infiltrating cellular immune responses that related to tissue degeneration. Increased anti-Gal antibody levels were found in serum after ATS 3f and Freedom/Solo implantation but not for Crown or Hancock II grafts. Overall, there were no correlations between cellular-immunity scores and post-implantation antibodies, suggesting these are independent factors differentially affecting the outcome of distinct commercial BHVs. These findings provide further insights into the understanding of SVD immunopathogenesis and highlight the need to evaluate immune responses as a confounding factor.

Correlations between the alpha-Gal antigen, antibody response and calcification of cardiac valve bioprostheses: experimental evidence obtained using an alpha-Gal knockout mouse animal model.

Introduction: Preformed antibodies against αGal in the human and the presence of αGal antigens on the tissue constituting the commercial bioprosthetic heart valves (BHVs, mainly bovine or porcine pericardium), lead to opsonization of the implanted BHV, leading to deterioration and calcification. Murine subcutaneous implantation of BHVs leaflets has been widely used for testing the efficacy of anti-calcification treatments. Unfortunately, commercial BHVs leaflets implanted into a murine model will not be able to elicit an αGal immune response because such antigen is expressed in the recipient and therefore immunologically tolerated. Methods: This study evaluates the calcium deposition on commercial BHV using a new humanized murine αGal knockout (KO) animal model. Furtherly, the anti-calcification efficacy of a polyphenol-based treatment was deeply investigated. By using CRISPR/Cas9 approach an αGal KO mouse was created and adopted for the evaluation of the calcific propensity of original and polyphenols treated BHV by subcutaneous implantation. The calcium quantification was carried out by plasma analysis; the immune response evaluation was performed by histology and immunological assays. Anti-αGal antibodies level in KO mice increases at least double after 2 months of implantation of original commercial BHV compared to WT mice, conversely, the polyphenols-based treatment seems to effectively mask the antigen to the KO mice's immune system. Results: Commercial leaflets explanted after 1 month from KO mice showed a four-time increased calcium deposition than what was observed on that explanted from WT. Polyphenol treatment prevents calcium deposition by over 99% in both KO and WT animals. The implantation of commercial BHV leaflets significantly stimulates the KO mouse immune system resulting in massive production of anti-Gal antibodies and the exacerbation of the αGal-related calcific effect if compared with the WT mouse. Discussion: The polyphenol-based treatment applied in this investigation showed an unexpected ability to inhibit the recognition of BHV xenoantigens by circulating antibodies almost completely preventing calcific depositions compared to the untreated counterpart.

Free-aldehyde neutralized and oligohyaluronan loaded bovine pericardium with improved anti-calcification and endothelialization for bioprosthetic heart valves.

The number of patients with valvular heart disease is increasing yearly, and valve replacement is the most effective treatment, during which bioprosthetic heart valves (BHVs) are the most widely used. Commercial BHVs are mainly prepared with glutaraldehyde (Glut) cross-linked bovine pericardial or porcine aortic valves, but the residual free aldehyde groups in these tissues can cause calcification and cytotoxicity. Moreover, insufficient glycosaminoglycans (GAGs) in tissues can further reduce biocompatibility and durability. However, the anti-calcification performance and biocompatibility might be improved by blocking the free aldehyde groups and increasing the GAGs content in Glut-crosslinked tissues. In our study, adipic dihydrazide (ADH) was used to neutralize the residual free aldehyde groups in tissues and provide sites to blind with oligohyaluronan (OHA) to increase the content of GAGs in tissues. The modified bovine pericardium was evaluated for its content of residual aldehyde groups, the amount of OHA loaded, physical/chemical characteristics, biomechanical properties, biocompatibility, and in vivo anticalcification assay and endothelialization effects in juvenile Sprague-Dawley rats. The results showed that ADH could completely neutralize the free aldehyde groups in the Glut-crosslinked bovine pericardium, the amount of OHA loaded increased and the cytotoxicity was reduced. Moreover, the in vivo results also showed that the level of calcification and inflammatory response in the modified pericardial tissue was significantly reduced in a rat subcutaneous implantation model, and the results from the rat abdominal aorta vascular patch repair model further demonstrated the improved capability of the modified pericardial tissues for endothelialization. Furthermore, more α-SMA+ smooth muscle cells and fewer CD68+ macrophages infiltrated in the neointima of the modified pericardial patch. In summary, blocking free-aldehydes and loading OHA improved the anti-calcification, anti-inflammation and endothelialization properties of Glut-crosslinked BHVs and in particularly, this modified strategy may be a promising candidate for the next-generation of BHVs.

Preliminary study of improving immune tolerance in vivo of bioprosthetic heart valves through a novel antigenic removal method.

The durability of bioprosthetic heart valves is always compromised by the inherent antigenicity of biomaterials. Decellularization has been a promising approach to reducing the immunogenicity of biological valves. However, current methods are insufficient in eliminating all immunogenicity from the biomaterials, necessitating the exploration of novel techniques. In this study, we investigated using a novel detergent, fatty alcohol polyoxyethylene ether sodium sulfate (AES), to remove antigens from bovine pericardium. Our results demonstrated that AES treatment achieved a higher pericardial antigen removal rate than traditional detergent treatments while preserving the mechanical properties and biocompatibility of the biomaterials. Moreover, we observed excellent immune tolerance in the in vivo rat model. Overall, our findings suggest that AES treatment is a promising method for preparing biological valves with ideal clinical application prospects.

The efficacy and safety of direct oral anticoagulants versus vitamin K antagonists in patients with left-sided bioprosthetic heart valves and atrial fibrillation: a systematic review and meta-analysis.

BACKGROUND: The efficacy and safety of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs) for the treatment of patients with left-sided bioprosthetic heart valves (BHV) and atrial fibrillation (AF) remain controversial. This study aims to perform a meta-analysis to evaluate the efficacy and safety of DOACs versus VKAs in this region. METHODS: We retrieved all relevant randomized controlled studies and observational cohort studies, which critically assessed the efficacy and safety of DOACs versus VKAs among patients with left-sided BHV and AF in databases of PubMed, Cochrane, ISI Web of Sciences, and Embase. The efficacy outcomes of this meta-analysis were stroke events and all-cause death when the safety outcomes included major and any bleeding. RESULTS: The analysis integrated 13 studies while enrolling 27,793 patients with AF and left-sided BHV. DOACs reduced the rate of stroke by 33% compared with VKAs (risk ratio [RR] 0.67; 95% CI 0.50-0.91), with no increased incidence of all-cause death (RR 0.96; 95% CI 0.82-1.12). For safety outcomes, major bleeding was reduced by 28% using DOACs rather than VKAs (RR 0.72; 95% CI 0.52-0.99), while there was no difference in the events of any bleeding (RR 0.84; 95% CI 0.68-1.03). In addition, in patients younger than 75 years old, the stroke rate was reduced by 45% in the population using DOACs (RR 0.55; 95% CI 0.37-0.84). CONCLUSION: Our meta-analysis demonstrated that in patients with AF and BHV, compared with VKAs, using DOACs was associated with reduced stroke and major bleeding events without an increase of all-cause mortality and any bleeding. In the population younger than 75 years old, DOAC might be more effective in preventing cardiogenic stroke.

Bioprosthetic heart valve structural degeneration associated with metabolic syndrome: Mitigation with polyoxazoline modification.

Bioprosthetic heart valves (BHV), made from glutaraldehyde-fixed xenografts, are widely used for surgical and transcatheter valve interventions but suffer from limited durability due to structural valve degeneration (SVD). We focused on metabolic syndrome (MetS), a risk factor for SVD and a highly prevalent phenotype in patients affected by valvular heart disease with a well-recognized cluster of comorbidities. Multicenter patient data (N = 251) revealed that patients with MetS were at significantly higher risk of accelerated SVD and required BHV replacement sooner. Using a next-generation proteomics approach, we identified significantly differential proteomes from leaflets of explanted BHV from MetS and non-MetS patients (N = 24). Given the significance of protein infiltration in MetS-induced SVD, we then demonstrated the protective effects of polyoxazoline modification of BHV leaflets to mitigate MetS-induced BHV biomaterial degeneration (calcification, tissue cross-linking, and microstructural changes) in an ex vivo serum model and an in vivo with MetS rat subcutaneous implants.

Proteolytic Degradation Is a Major Contributor to Bioprosthetic Heart Valve Failure.

Background Whereas the risk factors for structural valve degeneration (SVD) of glutaraldehyde-treated bioprosthetic heart valves (BHVs) are well studied, those responsible for the failure of BHVs fixed with alternative next-generation chemicals remain largely unknown. This study aimed to investigate the reasons behind the development of SVD in ethylene glycol diglycidyl ether-treated BHVs. Methods and Results Ten ethylene glycol diglycidyl ether-treated BHVs excised because of SVD, and 5 calcified aortic valves (AVs) replaced with BHVs because of calcific AV disease were collected and their proteomic profile was deciphered. Then, BHVs and AVs were interrogated for immune cell infiltration, microbial contamination, distribution of matrix-degrading enzymes and their tissue inhibitors, lipid deposition, and calcification. In contrast with dysfunctional AVs, failing BHVs suffered from complement-driven neutrophil invasion, excessive proteolysis, unwanted coagulation, and lipid deposition. Neutrophil infiltration was triggered by an asymptomatic bacterial colonization of the prosthetic tissue. Neutrophil elastase, myeloblastin/proteinase 3, cathepsin G, and matrix metalloproteinases (MMPs; neutrophil-derived MMP-8 and plasma-derived MMP-9), were significantly overexpressed, while tissue inhibitors of metalloproteinases 1/2 were downregulated in the BHVs as compared with AVs, together indicative of unbalanced proteolysis in the failing BHVs. As opposed to other proteases, MMP-9 was mostly expressed in the disorganized prosthetic extracellular matrix, suggesting plasma-derived proteases as the primary culprit of SVD in ethylene glycol diglycidyl ether-treated BHVs. Hence, hemodynamic stress and progressive accumulation of proteases led to the extracellular matrix degeneration and dystrophic calcification, ultimately resulting in SVD. Conclusions Neutrophil- and plasma-derived proteases are responsible for the loss of BHV mechanical competence and need to be thwarted to prevent SVD.

Age-related enhanced degeneration of bioprosthetic valves due to leaflet calcification, tissue crosslinking, and structural changes.

AIMS: Bioprosthetic heart valves (BHVs), made from glutaraldehyde-fixed heterograft materials, are subject to more rapid structural valve degeneration (SVD) in paediatric and young adult patients. Differences in blood biochemistries and propensity for disease accelerate SVD in these patients, which results in multiple re-operations with compounding risks. The goal of this study is to investigate the mechanisms of BHV biomaterial degeneration and present models for studying SVD in young patients and juvenile animal models. METHODS AND RESULTS: We studied SVD in clinical BHV explants from paediatric and young adult patients, juvenile sheep implantation model, rat subcutaneous implants, and an ex vivo serum incubation model. BHV biomaterials were analysed for calcification, collagen microstructure (alignment and crimp), and crosslinking density. Serum markers of calcification and tissue crosslinking were compared between young and adult subjects. We demonstrated that immature subjects were more susceptible to calcification, microstructural changes, and advanced glycation end products formation. In vivo and ex vivo studies comparing immature and mature subjects mirrored SVD in clinical observations. The interaction between host serum and BHV biomaterials leads to significant structural and biochemical changes which impact their functions. CONCLUSIONS: There is an increased risk for accelerated SVD in younger subjects, both experimental animals and patients. Increased calcification, altered collagen microstructure with loss of alignment and increased crimp periods, and increased crosslinking are three main characteristics in BHV explants from young subjects leading to SVD. Together, our studies establish a basis for assessing the increased susceptibility of BHV biomaterials to accelerated SVD in young patients.

Synthesis of High-Molecular-Weight and Strength Polyisobutylene-Based Polyurethane and Its Use for the Development of a Synthetic Heart Valve.

Under optimized synthesis conditions, for the first time, polyisobutylene-based polyurethane (PIB-PU) is prepared with 70% PIB soft segment (i.e., a bioinert and calcification-resistant PU) with Mn > 100 000 Da, 32 MPa ultimate strength, and 630% elongation. The key parameters for this achievement are a) the precise stoichiometry of the polyurethane forming reaction, specifically the use of highly purified di-isocyanate (4,4'-methylene-bis (phenyl isocyanate), MDI), and b) the increased solid content of the synthesis solution to the limit beyond which increased viscosity prevents stirring. The shape of the stress-strain trace of PIB-PU indicates a two-step failure starting with a reversible elastic (Hookean) region up to ≈50% yield, followed by a slower linearly increasing high-modulus-deformation region suggesting the strengthening of PIB soft segments by entanglement/catenation, and the hard segments by progressively ordering urethane domains. This PIB-PU is a candidate for a fully synthetic bioprosthetic heart valve since preliminary studies show that PIB-PU has impressive fatigue life.