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A New Type of Bioprosthetic Heart Valve: Synergistic Modification with Anticoagulant Polysaccharides and Anti-inflammatory Drugs

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Commercial glutaraldehyde (Glut) cross-linked bioprosthetic heart valves (BHVs) fabricated from the pericardium have become the most popular choice for treating heart valve diseases. Nevertheless, thrombosis, inflammation and calcification might lead to structural valve degeneration (SVD), which limited the durability of BHVs. Herein, to improve the biocompatibility of BHVs, we fabricated a poly-(2-methoxyethyl acrylate) (PMEA) coated porcine pericardium (PMEA-PP) through grafting PMEA to the porcine pericardium (PP) that was pre-treated with Glut and methacrylated polylysine. PMEA coating mitigated the side effects caused by aldehyde residues. It was shown that the PMEA coating reduced cytotoxicity and inflammation reactions and improved endothelialization potential, and its hydrophilic surface improved the anti-thrombotic properties of PPs. And the PMEA coating significantly reduced the calcification of PPs. This strategy promoted the endothelialization potential and improve the anti-thrombosis and anti-calcification properties of BHVs, and is expected to overcome the defects of commercial BHVs.
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Platelets exert an essential role in vascular inflammation and thrombosis. Flavonoids are natural compounds employed for the clinical management of vascular disorders preventing capillary permeability, working as phlebotonics and improving the blood rheology, although their mechanism of action remains partially unknown. The effects of quercetin, rutin, diosmetin and diosmin were investigated in platelet activation utilizing blood from healthy and non-treated volunteers. The arrangement of the different activation states of platelets and GPIIb/IIIa receptor occupation was computed by flow cytometry working with calcium ionophore as pro-aggregant to provoke platelet activation and aggregation. The flavonoids studied demonstrated relevant antiplatelet activity through the blocked of GPIIb/IIIa receptors, the suppression of the platelet activation, as well as the pro-aggregate effect of calcium ionophore. Therefore, whichever of the active ingredients examined could be beneficious in the prevention of cardiovascular disease and this article also contributes to elucidate a new mechanism of action for these drugs.
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BACKGROUND The American Heart Association, in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs). METHODS The American Heart Association, through its Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update. The 2021 Statistical Update is the product of a full year’s worth of effort by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. This year’s edition includes data on the monitoring and benefits of cardiovascular health in the population, an enhanced focus on social determinants of health, adverse pregnancy outcomes, vascular contributions to brain health, the global burden of cardiovascular disease, and further evidence-based approaches to changing behaviors related to cardiovascular disease. RESULTS Each of the 27 chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics. CONCLUSIONS The Statistical Update represents a critical resource for the lay public, policy makers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.
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Although transcatheter aortic valve implantation (TAVI) has been proven with excellent effectiveness and safety, the subclinical leaflet thrombosis (SLT) and structural valve deterioration (SVD) are two main factors threatening the service lifespan of the transcatheter aortic valve (TAV) because the glutaraldehyde (Glut) crosslinked tissue as leaflet material for the current clinically used TAV has high calcification propensity and thrombogenicity. In this study, zwitterionic monomer sulfobetaine methacrylate (SBMA) and methacrylated porcine pericardium (MA-PP) were in situ copolymerized to obtain zwitterionic-polymer/ tissue hybrid (PSBMA-PP). The hybrid PP showed high collagen stability, appropriate mechanical property, and anti-fatigue performance, meeting the essential requirements as a TAV leaflet. Moreover, the assays of platelet adhesion, in vitro thrombus generation, and ex vivo arteriovenous shunt (AV-shunt) assay suggested that PSBMA-PP had significantly lower thrombogenicity than the non-hybrid porcine pericardium (PMA-PP) and glutaraldehyde crosslinked porcine pericardium (Glut-PP). Interestingly, the introduction of poly-SBMA increased the resistance to the adsorption of non-specific proteins but didn’t compromise the endothelialization potential, promisingly benefitting the long-term hemocompatibility. Meanwhile, the subcutaneous implantation in rats for 120 days showed that PSBMA-PP was able to effectively inhibit the calcification of valve leaflets compared with Glut-PP, which was significant to retard the occurrence of SVD. In conclusion, we developed a simple method to simultaneously functionalize and crosslink the tissue with robust antithrombotic and anticalcification properties for the fabrication of TAV, which was expected to further improve the safety and service life of existing interventional TAV products.
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Alibertia edulis leaf extract (AELE) is commonly used in folk medicine, with rutin being its major compound. The AELE was investigated from its pharmacological effects via platelet aggregation, calcium mobilization, cyclic nucleotides levels, VASP157, VASP239 and PKCβ2 phosphorylation, thromboxane B2 (TXB2), cyclooxygenases (COX-1 and COX-2) and docking and molecular dynamics simulations were evaluated. AELE significantly inhibited (100-1000 μg/mL) platelet aggregation induced by different agonists. AA increased levels of Ca²⁺ and TXB2, phosphorylation of VASP157, VASP239 and PKCβ2, which were significantly reduced by AELE and rutin. COX-1 activity was inhibited for both AELE and rutin. This inhibition was explored by specific stabilization of rutin at the catalytic site, close to the heme group and Tyr385, responsible for catalyzing the conversion of AA to its products. Our results discuss the antiplatelet aggregation property of AELE and rutin and provide pharmacological information about its origin from COX-1 inhibition and its downstream pathway.
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Bioprosthetic valves (BPVs) have a limited lifespan in the body necessitating repeated surgeries to replace the failed implant. Early failure of these implants has been linked to various surface properties of the valve. Surface properties of BPVs are significantly different from physiological valves because of the fixation process used when processing the xenograft tissue. To improve the longevity of BPVs, efforts need to be taken to improve the surface properties and shield the implant from the bodily interactions that degrade it. Toward this goal, we evaluated the use of hydrogel coatings to attach to the BPV tissue and impart surface properties that are close to physiological. Hydrogels are well characterized for their biocompatibility and highly tunable surface characteristics. Using a previously published coating method, we deposited hydrogel coatings of poly(ethylene glycol)diacrylate (PEGDA) and poly(ethylene glycol)diacrylamide (PEGDAA) atop BPV samples. Coated samples were evaluated against the physiological tissue and uncoated glutaraldehyde-fixed tissue for deposition of hydrogel, surface adherence, mechanical properties, and fixation properties. Results showed both PEGDA- and PEGDAA-deposited coatings were nearly continuous across the valve leaflet surface. Further, the PEGDA- and PEGDAA-coated samples showed restoration of physiological levels of protein adhesion and mechanical stiffness. Interestingly, the coating process rather than the coating itself altered the material behavior yet did not alter the cross-linking from fixation. These results show that the PEG-based coatings for BPVs can successfully alter surface properties of BPVs and help promote physiological characteristics without interfering with the necessary fixation.
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In this work, the solubility of rutin was first obtained in the water-ethanol solvents with small composition of co-solvent in the mixture at 25 °C. The results showed that the solubility of rutin improved with increasing ethanol content in the studied range 0–0.1 mol. fr. Solvation of hydroxypropyl-β-cyclodextrin in binary solvents was first studied by the method of interfacial distribution of the substance between two immiscible phases. It was found that when moving hydroxypropyl-β-cyclodextrin from water to the water-ethanol solvent, a decrease in the solvation of hydroxypropyl-β-cyclodextrin was observed. Complexation between rutin and β-cyclodextrin or hydroxypropyl-β-cyclodextrin was also studied in water and in the water-ethanol solvents. In the aqueous solution containing hydroxypropyl-β-cyclodextrin, the solubility of rutin was improved significantly and better than in the solution containing β-cyclodextrin. The stability of (rutin-hydroxypropyl-β-cyclodextrin) complex decreased with increasing the ethanol content and was determined by the sum of solvation of rutin (ΔtrGRuT) and hydroxypropyl-β-cyclodextrin (ΔtrGHPβCD). This effect was also observed for the complexation reaction between quercetin and hydroxypropyl-β-cyclodextrin in our previous study.
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As transcatheter aortic valve replacement becomes a more dominant treatment option across all risk profiles, the frequency of encountering patients with multivalvular disease will increase. Furthermore, percutaneous interventions to treat other valvular lesions are also evolving. Understanding the clinical implications and treatment options for a second valvular lesion is becoming increasingly important to guide heart team decisions, and this paper aims to review the evidence around these situations. Diagnosis of multivalvular disease can be challenging because of changes in physiology. There are little randomized data to guide therapy in multivalvular disease. Multidisciplinary heart team decisions can be invaluable in integrating the plethora of clinical, hemodynamic, and imaging data on which an optimal management strategy can be planned. Prospective studies to assess the role of structural valve interventions in the transcatheter aortic valve replacement era would greatly help improve outcomes for structural heart patients.
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The objective of this study was to evaluate the effect of chemical treatment with glutamic acid to avoid the calcification of biological cardiac valves. The bovine pericardium (BP) tissues were fixed with 0.5% glutaraldehyde (BP/GA), followed by treatment with glutamic acid (BP/GA+Glu) for neutralization of the free aldehydes groups. Microscopic analysis showed that the wavy structure of collagen fibrils was preserved, but changes in elastin’s integrity occurred. However, the treatment did not promote undesirable changes in the thermal and mechanical properties of the modified BPs. These samples were systematically studied in rat subcutaneous tissue: control (BP/GA) and anticalcificant (BP/GA+Glu). After 60 days, both groups induced similar inflammatory reactions. In terms of calcification, BP/GA+Glu remained more stable with a lower index (3.1 ± 0.2 μg Ca2+/mg dry tissue), whereas for BP/GA it was 5.7 ± 1.3 μg Ca2+/mg dry tissue. Bioprostheses made from BP/GA+Glu were implanted in the pulmonary position in sheep and in vivo echocardiographic analyzes revealed maintenance of valvar function after 180 days, with low gradients and minimal valve insufficiency. The explanted tissues of the BP/GA+Glu group had a lower average calcium content 3.8 ± 3.0 μg Ca2+/mg dry tissue. The results indicated high anticalcification efficiency of BP/GA+Glu in both subcutaneous implant in rats and in the experimental study in ovine, which is an advantage that should encourage the industrial application of these materials for the manufacture of bioprostheses.
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Recent trials have shown impressive results in low-risk patients undergoing Transcatheter Aortic Valve Replacement (TAVR) with low procedural complication rates, short hospital length of stay, zero mortality, and zero disabling stroke at 30 days and have led to a Food and Drug Administration indication for TAVR in these patients. The long-term data on subclinical leaflet thrombosis, valve durability, effects of pacemaker implantation, right ventricular pacing, and progressive paravalvular leak is unclear. We describe clinical and procedural considerations for patient selection and introduce future potential procedural challenges. Finally, we discuss the importance of considering life expectancy and durability prior to TAVR in this low risk relatively young cohort and emphasize the importance of a heart team approach.
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The lifetime of bioprosthetic heart valves (BHVs) is limited by the mechanical damage and calcification. The major components of BHVs are collagen and elastin. Collagen could be well protected by glutaraldehyde (GLUT) crosslinking, while elastin is not stabilized and has a high risk of degradation, which could lead to the calcification of BHVs. We aimed to develop methods for stabilizing elastin and decreasing calcification. We investigated the combined tannic acid (TA) or epigallocatechin gallate (EGCG) with ferric chloride to stabilize elastin and prevent calcification. We found that the amount of TA/EGCG bound to elastin was in a time‐dependent pattern and this reaction showed better efficiency in acidic condition and ethanol‐water mixed solvents. Moreover, Fe3+ could compete with Ca2+ to bind to polyphenol, which could reduce the calcium deposition on BHVs. Cytotoxicity test showed that all extracts from different treatments had similar cell viabilities (85–100%). Through the combined treatments of polyphenol and ferric chloride, the pericardium had a better resistance to elastase degradation and more excellent anticalcification performance.
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Tissue engineered vascular grafts (TEVGs) are beginning to achieve clinical success and hold promise as a source of grafting material when donor grafts are unsuitable or unavailable. Significant technological advances have generated small‐diameter TEVGs that are mechanically stable and promote functional remodeling by regenerating host cells. However, developing a biocompatible blood‐contacting surface remains a major challenge. The TEVG luminal surface must avoid negative inflammatory responses and thrombogenesis immediately upon implantation and promote endothelialization. The surface has therefore become a primary focus for research and development efforts. The current state of TEVGs is herein reviewed with an emphasis on the blood‐contacting surface. General vascular physiology and developmental challenges and strategies are briefly described, followed by an overview of the materials currently employed in TEVGs. The use of biodegradable materials and stem cells requires careful control of graft composition, degradation behavior, and cell recruitment ability to ensure that a physiologically relevant vessel structure is ultimately achieved. The establishment of a stable monolayer of endothelial cells and the quiescence of smooth muscle cells are critical to the maintenance of patency. Several strategies to modify blood‐contacting surfaces to resist thrombosis and control cellular recruitment are reviewed, including coatings of biomimetic peptides and heparin.
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Several lines of evidence suggest that flavonoids that originated from vegetables and medicinal plants have beneficial effects on diabetes by improving glycemic control, lipid profile, and antioxidant status. Rutin is a flavonoid found in many plants and shows a wide range of biological activities including anti-inflammatory, antioxidant, neuroprotective, nephroprotective, and hepatoprotective effects. In this review, the antihyperglycemic property of rutin and its protective effects against the development of diabetic complications are discussed. Proposed mechanisms for the antihyperglycemic effect of rutin include a decrease of carbohydrates absorption from the small intestine, inhibition of tissue gluconeogenesis, an increase of tissue glucose uptake, stimulation of insulin secretion from beta cells, and protecting Langerhans islet against degeneration. Rutin also decreases the formation of sorbitol, reactive oxygen species, advanced glycation end-product precursors, and inflammatory cytokines. These effects are considered to be responsible for the protective effect of rutin against hyperglycemia- and dyslipidemia-induced nephropathy, neuropathy, liver damage, and cardiovascular disorders. Taken together, the results of current experimental studies support the potential of rutin to prevent or treat pathologies associated with diabetes. Well-designed clinical studies are suggested to evaluate advantages and limits of rutin for managing diabetes.
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Although surgery was the mainstay of treatment for valvular heart disease, transcatheter valve therapies have grown exponentially over the past decade. Two types of artificial heart valve exist: mechanical heart valves (MHV), which are implanted surgically, and bioprosthetic heart valves (BHV), which can be implanted via a surgical or transcatheter approach. Whereas long-term anticoagulation is required to prevent thromboembolism after MHV replacement, its value in patients receiving BHVs is uncertain. Patients undergoing transcatheter BHV replacement are at risk for thromboembolism in the first few months, and recent data suggest that the risk continues thereafter. BHV thrombosis provides a substrate for subsequent thromboembolism and may identify a reversible cause of prosthesis dysfunction. Hereafter, the authors: 1) review the data on prosthetic valve thrombosis; 2) discuss the pathophysiological mechanisms that may lead to valve thrombus formation; and 3) provide perspective on the implications of these findings in the era of transcatheter valve replacement.
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Thrombosis and calcification constitute the main clinical problems when blood-interacting devices are implanted in the body. Coatings with thin polymer layers represent an acknowledged strategy to modulate interactions between the material surface and the blood environment. To ensure the implant success, at short-term the coating should limit platelets adhesion and delay the clot formation, and at long-term it should delay the calcification process. Sulfonated chitosan, if compared to native chitosan, shows the unique ability to reduce proteins adsorption, decrease thrombogenic properties and limit calcification. In this work, stainless steel surfaces, commonly used for cardiovascular applications, were coated with sulfonated chitosan, by using dopamine and PEG as anchors, and the effect of these grafted surfaces on platelet adhesion, clot formation as well as on calcification were investigated. Surface characterization techniques evidenced that the coating formation was successful, and the sulfonated chitosan grafted sample exhibited a higher roughness and hydrophilicity, if compared to native chitosan one. Moreover, sulfonated surface limited platelet activation and the process of clot formation, thus confirming its high biological performances in blood. Calcium deposits were also lower on the sulfonated chitosan sample compared to the chitosan one, thus showing that calcification was minimal in presence of sulfonate groups. In conclusion, this sulfonated-modified surface has potential to be as blood-interacting material.
Article
One-step self-assembly was used to prepare pH-sensitive lappaconitine-loaded low-molecular-weight heparin (LMWH-LA) and to demonstrate that the sulfur group promotes dissolution and has synergistic effect on the analgesic property of lappaconitine (LA). The LMWH-LA was characterized in terms of releasing behavior, pH-sensitivity, analgesic activity and anticoagulation property. The drug loading level of LA in low-molecular-weight heparin (LMWH) reached 24.3% (w/w). The LA, self-assembled in LMWH, released faster in an acidic environment than that in neutral or alkaline environments. Analgesic experiments showed that the LMWH-LA had earlier onset time and longer duration than the LA. Compared with LMWH, the LMWH-LA can reduce clotting time more effectively. These results suggest that the LMWH is a good template and has great potential to achieve synergistic effect of LA. In addition, similar macromolecular structure can be used as a new natural polymeric carrier for loading hydrophobic alkaloids.
Article
In this study, cyclodextrin inclusion complexes with rutin were prepared via co-precipitation method. Stability constant and solubility energy of beta-cyclodextrin complex were calculated as 262 M-1 and 1,737 kJ mol(-1), respectively. Aqueous solubility of rutin was increased with inclusion complex of beta-cyclodextrin. The effect of temperature on both aqueous solubility of free rutin, and its inclusion complex was also studied. Characterization of cyclodextrin complexes were conducted with UV-Vis spectrophotometry, Fourier transform infrared spectroscopy, X-ray diffractometry, differential scanning calorimetry, thermal gravimetric analysis, nuclear magnetic resonance spectroscopy and scanning electron microscopy techniques. Characterization results supported formation of inclusion complexes. Dissolution profiles of rutin, physical mixture and inclusion complex of rutin were observed at 37 A degrees C. Dissolution results proved the effect of cyclodextrin addition on solubility rate of rutin. After loading rutin and its complexes into silk fibroin based films, release tests were performed at 37 A degrees C in neutral pH conditions for 24 h. Most of the rutin were released from silk fibroin films within the first 5 h and the rest of it was released slowly (sustained release). Electron microscope analyses showed that films had homogenous and dense morphologies. These results revealed that silk fibroin is useful for preparing bioactive films loaded with natural compounds and for modifying their release behaviour at physiological conditions.
Article
Ethnopharmacological relevance: Rutin is a common dietary flavonoid that is widely consumed from plant-derived beverages and foods as traditional and folkloric medicine worldwide. Rutin is believed to exhibit significant pharmacological activities, including anti-oxidation, anti-inflammation, anti-diabetic, anti-adipogenic, neuroprotective and hormone therapy. Till date, over 130 registered therapeutic medicinal preparations are containing rutin in their formulations. This article aims to critically review the extraction methods for plant-based rutin and its pharmacological activities. This review provides comprehensive data on the performance of rutin extraction methods and the extent of its pharmacological activities using various in vitro and in vivo experimental models. Materials and methods: Literatures including journals, patents, books and leaflets reporting on rutin from natural resources are systematically reviewed, particularly in the aspect of its extraction methods and biological activities. Factors affecting the efficiency of rutin extraction such as extraction temperature, duration and solvent to sample ratio are presented based on the findings of previous studies. The observed biological activities followed by clear explanation are also provided accordingly. Results: The biological activities of rutin varied largely dependent on the geographical and plant origins. The complexity of natural rutin has impeded the development of rutin derived drugs. The detail mechanism of rutin in human body after consumption is still unclear. Therefore, studies are intensively carried out both in vitro and in vivo for the better understanding of the underlying mechanism. The studies are not limited to the pharmacological properties, but also on the extraction methods of rutin. Many studies have focused on the optimization of extraction method to increase the extraction yield of rutin. Currently, the performances of modern extraction approaches have also been compared to the conventional heat reflux method as a benchmark. Conclusion: There are various extraction methods for plant-based rutin ranging from conventional method up to the use of modern techniques such as ultrasound, mechanochemical, microwave, infrared and pressurized assisted methods. However, proper comparison between the methods is very difficult because of the variance in plant origin and extraction conditions. It is important to optimize the extraction method in order to produce high yield and acceptable purity of rutin with a reasonable cost. Even though rutin has been proven to be effective in numerous pharmacological activities, the dosage and toxicity of rutin for such activities are still unknown. Future research should relate the dosage and toxicity of rutin for the ethnobotanical claims based on the underlying mechanisms.
Article
Glutaraldehyde cross-linked porcine aortic valves, referred to as bioprosthetic heart valves (BHVs), are often used in heart valve replacements. Glutaraldehyde does not stabilize glycosaminoglycans (GAGs) and they are lost during preparation, in vivo implantation, cyclic fatigue, and storage. We report that binding of neomycin, a hyaluronidase inhibitor, to the tissues with carbodiimide cross-linking improves GAG retention without reducing collagen and elastin stability. It also led to improved biomechanical properties. Neomycin carbodiimide cross-linking did not significantly reduce calcification in a rat subdermal implantation model when they were stored in formaldehyde after cross-linking. Removal of formaldehyde storage significantly reduced calcification.
Article
Glutaraldehyde crosslinked bioprosthetic heart valves (BHVs) have two modalities of failure: degeneration (cuspal tear due to matrix failure) and calcification. They can occur independently as well as one can lead to the other causing co-existence. Calcific failure has been extensively studied before and several anti-calcification treatments have been developed; however, little research is directed to understand mechanisms of valvular degeneration. One of the shortcomings of glutaraldehyde fixation is its inability to stabilize all extracellular matrix components in the tissue. Previous studies from our lab have demonstrated that neomycin could be used as a fixative to stabilize glycosaminoglycans (GAGs) present in the valve to improve matrix properties. But neomycin fixation did not prevent cuspal calcification. In the present study, we wanted to enhance the anti-calcification potential of neomycin fixed valves by pre-treating with ethanol or removing the free aldehydes by sodium borohydride treatment. Ethanol treatment has been previously used and found to have excellent anti-calcification properties for valve cusps. Results demonstrated in this study suggest that neomycin followed by ethanol treatment effectively preserves GAGs both in vitro as well as in vivo after subdermal implantation in rats. In vivo calcification was inhibited in neomycin fixed cusps pretreated with ethanol compared to glutaraldehyde (GLUT) control. Sodium borohydride treatment by itself did not inhibit calcification nor stabilized GAGs against enzymatic degradation. Neomycin fixation followed by ethanol treatment of BHVs could prevent both modalities of failure, thereby increasing the effective durability and lifetime of these bioprostheses several fold.
Article
Sulfated polysaccharides from 11 species of tropical marine algae (one edible specie of Rhodophyta, six species of Phaeophyta and four species of Chlorophyta) collected from Natal city coast (Northeast of Brazil) were evaluated for their anticoagulant, antioxidant and antiproliverative in vitro activities. In the activated partial thromboplastin time (APTT) test, which evaluates the intrinsic coagulation pathway, seven seaweeds presented anticoagulant activity. Dictyota cervicornis showed the highest activity, prolonging the coagulation time to double the baseline value in the APTT with only 0.01 mg/100 microl of plasma, 1.4-fold lesser than Clexane, a low molecular weight heparin. In the protrombin time (PT) test, which evaluates the extrinsic coagulation pathway, only Caulerpa cupresoides showed anticoagulant activity. All species collected showed antioxidant activities. This screening emphasized the great antioxidant potential (total capacity antioxidant, power reducing and ferrous chelating) of four species: C. sertularioide; Dictyota cervicornis; Sargassum filipendula and Dictyopteris delicatula. After 72 h incubation, HeLa cell proliferation was inhibited (p<0.05) between 33.0 and 67.5% by S. filipendula; 31.4 and 65.7% by D. delicatula; 36.3 and 58.4% by Caulerpa prolifera and 40.2 and 61.0% by Dictyota menstrualis at 0.01-2mg/mL algal polysaccharides. The antiproliferative efficacy of these algal polysaccharides were positively correlated with the sulfate content (r=0.934). Several polysaccharides demonstrated promising antioxidant, antiproliferative an/or anticoagulant potential and have been selected for further studies on bioguided fractionation, isolation and characterization of pure polysaccharides from these species as well as in vivo experiments are needed and are already in progress.
Article
Porcine aortic valve (AoF) tissues cross-linked with glutaraldehyde and epoxy compounds were reported to have high anticalcification properties, but their hydrodynamic characteristics have not been evaluated. The aim of the present study was to investigate the hydrodynamic differences between porcine AoFs, cross-linked with concomitant use of an epoxy compound and glutaraldehyde, at different fixation periods. The valves were mounted on a pulsatile flow circulation mimicking a left heart. The left atrial and left ventricular pressures and mitral and aortic flows were measured at every 0.002 seconds, and the hydrodynamic factor of the valves mounted on the mitral position was estimated. Effective orifice area and the regurgitation volume, which are used as indicators of valve efficiency, failed to detect significant differences due to glutaraldehyde fixation time. In addition, the pressure gradient across the bioprosthetic valve and the variation of mitral flow also had no significant differences. The flow circuit model of the present study was mimicking of a left heart. The evaluation of the mitral valvular function with different glutaraldehyde fixation times was accomplished by relating the pressure with the flow, and by estimating the time lag between valve motion and transvalvular flow.
Article
This study was designed to evaluate a newly developed biologic valved conduit fixed with genipin used to reconstruct the right ventricular outflow tract in a canine model. Fresh bovine jugular veins with a retained native valve procured from a slaughterhouse were used as raw materials to fabricate the valved conduits. A naturally occurring crosslinking agent, genipin, was used to fix the procured jugular veins. The glutaraldehyde-fixed counterpart was used as a control. A canine model was used in the study. Echocardiography revealed that the motion of the valvular leaflets in both the glutaraldehyde- and genipin-fixed conduits was satisfactory. The transvalvular pressure gradients of both studied groups were minimal. No endothelium-like cells were observed on the luminal surface of the conduit and the valvular leaflet for the glutaraldehyde-fixed group throughout the entire course of the study. In contrast, endothelium-like cells were observed on the entire surface of the genipin-fixed valved conduit retrieved at 6 months postoperatively in all the cases studied. There was no evidence of luminal fibrous peel in any the valved conduits studied. Degradation of valvular leaflet in one of the glutaraldehyde-fixed conduits was observed. In this particular case, thrombus formation was also observed on the surface of the valvular leaflet. On the other hand, no apparent degradation or thrombus formation was observed on the surfaces of the genipin-fixed valvular leaflet and conduit. A significantly more severe inflammatory reaction was observed for the glutaraldehyde-fixed conduit than for its genipin-fixed counterpart throughout the entire course of the study. The calcium contents of the samples before implantation and those retrieved at distinct implantation duration were minimal for both the glutaraldehyde- and genipin-fixed tissues. Although further studies are necessary, the genipin-fixed valved conduit appears to have great potential in helping mitigate the complications observed in the commercially available conduits.
Article
A novel chemical modification of biological tissues was developed by the direct coupling of bioactive molecule, L-arginine to bovine pericardium (BP). The modification involves pretreatment of BP using GA and followed by grafting arginine to BP by the reaction of residual aldehyde and amine group of L-arginine. BP was modified by direct coupling of bioactive molecules and the effect of L-arginine coupling on calcification and biocompatibility was evaluated in vitro and in vivo. Modified BPs were characterized by measuring shrinkage temperature, mechanical properties, digestion resistance to collagenase enzyme, in vitro plasma protein adsorption and platelet adhesion, and in vivo calcification. Thermal and mechanical properties showed that the durability of arginine treated tissue increased as compared with fresh tissue and GA treated tissue. Resistance to collagenase digestion revealed that modified tissues have greater resistance to enzyme digestion than did fresh tissue and GA treated tissue. Lower protein adsorption and platelet adhesion were observed on modified tissue than non-modified tissue. In vivo calcification study demonstrated much less calcium deposition on arginine treated BP than GA treated one. Obtained results attest to the usefulness of L-arginine treated BP for cardiovascular bioprostheses.
Article
Heart valve diseases have a significant high mortality, and the valve replacement using glutaraldehyde crosslinked porcine heart valves is one of the main curing techniques. But its application is limited due to poor durability, calcification of the valves and immunogenic reactions. The aim of this study was to evaluate the crosslinking effect of procyanidins on porcine heart valve matrix. After crosslinking of the decellularized porcine aortic heart valves by procyanidins, the tensile strength, the in vitro enzymatic degradation resistance, procyanidins release from the crosslinked materials and the cytotoxicity of procyanidins to heart valvular interstitial cells were examined. The results showed that the tensile strength of procyanidins crosslinked valve matrix was higher than that of glutaraldehyde crosslinked valve matrix. Valve matrix crosslinked by 10 mg/ml procyanidins could be stored in D-Hanks solution for at least 45 days without any decline in ultimate tensile strength and maintained the elasticity as the fresh valves. Furthermore, procyanidins was found to release when the crosslinked tissue stored in D-Hanks solution. The release rate was high during the first 4 days and then dramatically decreased thereafter. During releasing phase, the concentration of procyanidins was no toxicity to heart valve interstitial cells. In vitro enzymatic degradation revealed that crosslinked matrix could resist the enzymatic hydrolysis, and the resistant capacity was approximately the same as glutaraldehyde crosslinked valve matrix. This study shows that procyanidins can crosslink porcine heart valves effectively without toxicity. Our results suggested that this method might be a useful approach for preparation of bioprosthetic heart valve.