Valve Tissue Research Articles

The Quality of Life in Patients With Valve Prosthesis After Undergoing Surgery for Valvular Heart Diseases.

Background and objective Surgery for valvular heart disease by valve replacement procedures has become one of the most frequently performed cardiac operations to improve the quality of life (QoL). Its long-term outcomes are assessed using the quality-of-life index (QLI). This study aimed to evaluate the QoL in patients whoreceived valve prostheses after surgery for valvular heart diseases at King Abdulaziz University inJeddah from 2010 to 2023. Methods This was adescriptive cross-sectional study of 59 patients aged 18 years or older who underwent surgical mitral and aortic valve replacement, involving either mechanical or tissue valves,from January 2010 to May 2023 They were selectedusing a non-probability convenient sampling technique. Their medical records were reviewed and the participants were interviewed via phone using the World Health Organization Quality of Life-BREF (WHOQOL-BREF) questionnaire, which was used to measure the QoL of patients (https://neurotoolkit.com/whoqol-bref/). Results The study found that the QoL of the participants varied across different domains. The psychological domain had the highest mean score of 79.76, while the physical domain had the lowest mean score of 61.5. The other domains, - social, environmental, and spiritual - had mean scores of 68.05, 69.9, and 73.25, respectively. There was a statistically significant association between the QoL and nationality and chronic diseases. However, the duration after surgery and the type of valve did not significantly correlate with the QoL in the different domains. Conclusion Based on our findings, heart valve replacement improves the QoL of patients. Healthcare organizations and providers should aim to improve the management of chronic diseases to optimize outcomes.

Abstract P3031: The Cross Talk Between Increased Abdominal Adiposity And Calcification Of Aortic Valve

Calcified aortic valve disease (CAVD) is the most prevalent valvular heart disease in western populations affecting nearly 2.5% of individuals over 65. Currently, there is no viable pharmacological treatment to stop the disease's progression or activate mineral regression. The only effective therapy to treat CAVD is surgical valve replacement or trans-catheterization. Obesity is the major common nutritional disorder worldwide and is one of the important risk factors for CAVD. It has been shown that DLK1-/- mice have increased abdominal adiposity. Indeed Dlk1 plays an essential role in regulating adipocytes differentiation and proliferation. Recently, it has been shown that there is an association between fat tissue accumulation and an increased risk of aortic stenosis. We hypothesize that dysregulation of DLK1 stimulates adiposity, increases circulating lipids, enhances valve lipids retention, and stimulates calcification. Herein, our objective is to examine the expression of DLK1 in calcified aortic valves and its impact on lipid retention. Method: We examined the effect of Dlk1 loss of function on lipid retention in aortic valve tissue in ApoE-/- Dlk1-/- mice fed with a high-fat diet and in human explanted aortic valves using immuno-staining. Results: The complete deletion of DLK-1 in ApoE-/- mice were associated with an increased oxidized-LDL deposit in aortic valve tissue. In addition, circulating cholesterol (420 ± 8 mg/dl vs 250± 12 mg/dl, P=0.002) and triglyceride concentration (200 ± 3 mg/dl vs 50± 10 mg/dl, P<0.001) were higher in ApoE-/- DLK1-/- compared to apoE-/- mice. An increased valvular calcification accompanied these changes, as shown by the over-expression of RUNX2 and the increased aortic jet velocity in ApoE-/- DLK1-/- mice. Interestingly the overexpression of DLK1 in isolated human valve cells decreased calcification and lipid retention in vitro. Conclusion: This study showed the significant role of Dlk1-derived abdominal adiposity in valve-lipid retention and calcification.

IN SILICO MODELING OF PORCINE PERICARDIAL TISSUE LEAFLETS FOR TRANSCATHETER MITRAL VALVE REPLACEMENT

Tissue valve in combination with a mechanical valve is predominantly used in stented valvular prostheses. Porcine pericardium (PP) is a promising xenograft in addition to the predominately used porcine aortic valve (PAV) and bovine pericardium (BP) in heart valve replacement. Tissue valves are structurally similar to the valve cusps, upon fixation they function as structural and functional units to restore the failing heart valves. In this paper, the characterization, design and performance of PP based prosthetic mitral leaflets are analyzed. Uniaxial tensile test was performed to characterize glutaraldehyde (GA)-treated PP and evaluate its mechanical properties. Finite element methods were instrumental to design and analyze the performance of PP leaflets. Different geometric parameters were analyzed to obtain ideal valve performance. Since geometrical parameters influence valve performance, two leaflet models of trileaflet and quadrileaflet configuration were studied. BP and PAV leaflet models were designed and analyzed as controls to compare the performance of PP. The stress distribution, bending momentum and coaptation pattern from the finite element determine the performance of the geometrical models. PP exhibited anisotropy, promising tensile strength and pliability. A thinner porcine pericardium with promising tensile strength and pliability is ideal for the development of low-profile prosthetic valves. The quadrileaflet model exhibited.

Engineered Extracellular Vesicle-Based Therapies for Valvular Heart Disease.

Valvular heart disease represents a significant burden to the healthcare system, with approximately 5 million cases diagnosed annually in the US. Among these cases,calcific aortic stenosis (CAS) stands out as the most prevalent form of valvular heart disease in the aging population. CAS is characterized by theprogressive calcification of the aortic valve leaflets,leading to valve stiffening. While aortic valve replacement is the standard of care for CAS patients, the long-term durability of prosthetic devices is poor, calling for innovative strategies to halt or reverse disease progression. Here, we explor the potentialuse of novel extracellular vesicle (EV)-based nanocarriers for delivering molecular payloads to the affected valvetissue. This approach aims to reduce inflammation and potentially promote resorption of the calcified tissue. Engineered EVs loaded with the reprogramming myeloid transcriptionfactors, CEBPA and Spi1, known tomediatethe transdifferentiation of committed endothelialcells into macrophages. We evaluated the ability of these engineered EVs to deliver DNA and transcripts encoding CEBPA and Spilinto calcified aortic valve tissue obtainedfrom patients undergoing valve replacement due to aortic stenosis.We also investigated whether these EVs could induce the transdifferentiation of endothelial cells into macrophage-like cells. Engineered EVs loaded with CEBPA + Spi1 were successfully derived from human dermal fibroblasts. Peak EV loading was found to be at 4h after nanotransfection of donor cells. TheseCEBPA + Spi1 loaded EVs effectively transfected aortic valve cells, resulting in thesuccessful induction oftransdifferentiation, both in vitro with endothelial cells and ex vivo withvalvular endothelial cells, leading to the development ofanti-inflammatory macrophage-like cells. Our findings highlight the potential of engineered EVs as a next generation nanocarrier to target aberrant calcifications on diseased heart valves. This development holds promise asa novel therapy for high-risk patientswho may not be suitable candidates for valve replacement surgery. The online version contains supplementary material available at 10.1007/s12195-023-00783-x.

Antithrombotic therapy with Transcatheter aortic valve replacement.

Aortic valve replacement is a necessary management strategy for patients with severe aortic stenosis. The use of transaortic valve replacement (TAVR) has increased significantly over the last decade and now exceeds traditional surgical aortic valve replacement. Since the valve systems used in TAVR consist of bioprosthetic valve tissue encased in a metal stent frame, antithrombotic therapy recommendations cannot be extrapolated from prior data with differently constructed surgical bioprosthetic or mechanical valves. Data on the use of antithrombotic therapy with TAVR are a rapidly developing area of medicine. Choice of agents depends on several patient factors. Patients undergoing TAVR also have a relatively high incidence of subclinical valve thrombosis. The clinical impact of this phenomenon and the implications for antithrombotic therapy continue to evolve. It is critical for clinicians who treat patients undergoing TAVR to have a firm understanding of practice guidelines, the evolving evidence, and its implications for the use of antithrombotic therapy in these patients.

Intractable complicated course of tricuspid valve infective endocarditis due to non-compliance of treatment with clinical guidelines with a decisive role of molecular biological study in etiological diagnosis: a case report

A clinical observation of the treatment non-compliance consequences with clinical guidelines and principles of empirical therapy selection in a female patient with intravenous drug abuse, viral hepatitis C and HIV infection, with a history of a COVID-19 and the development of uncontrolled staphylococcal infective endocarditis (IE) of the tricuspid valve, complicated recurrence of early prosthetic IE is presented. Successful treatment was achieved only by a combination of tricuspid valve replacement and the appointment of etiotropic therapy for S. aureus (MSSA). The typical clinical scenario was not accompanied by the choice of adequate empirical antibiotic therapy, despite the high suspicion of association with MSSA, which determined the complicated course of IE. Only the polymerase chain reaction of the heart valve tissue played a key role in the etiological diagnosis. The use of valve tissue polymerase chain reaction in addition to traditional microbiological methods is a valuable diagnostic study.

Oxidized phospholipids facilitate calcific aortic valve disease by elevating ATF4 through the PERK/eIF2α axis.

In this study we sought to analyze the critical role of oxidized phospholipid (OxPL) in the progression of calcific aortic valve disease (CAVD) with the involvement of activating transcription factor 4 (ATF4). Differentially expressed genes related to CAVD were identified using bioinformatics analysis. Expression of ATF4 was examined in mouse models of aortic valve calcification (AVC) induced by the high cholesterol (HC) diet. Valvular interstitial cells (VICs) were then isolated from mouse non-calcified valve tissues, induced by osteogenic induction medium (OIM) and co-cultured with OxPAPC-stimulated macrophages. The effect of OxPLs regulating ATF4 on the macrophage polarization and osteogenic differentiation of VICs was examined with gain- and loss-of-function experiments in VICs and in vivo. In aortic valve tissues and OIM-induced VICs, ATF4 was highly expressed. ATF4 knockdown alleviated the osteogenic differentiation of VICs, as evidenced by reduced expression of bone morphogenetic protein-2 (BMP2), osteopontin (OPN), and osteocalcin. In addition, knockdown of ATF4 arrested the AVC in vivo. Meanwhile, OxPL promoted M1 polarization of macrophages and mediated osteogenic differentiation of VICs. Furthermore, OxPL up-regulated ATF4 expression through protein kinase R-like endoplasmic reticulum kinase (PERK)/eukaryotic translation initiation factor 2 subunit alpha (eIF2α) pathway. In conclusion, OxPL can potentially up-regulate the expression of ATF4, inducing macrophages polarized to M1 phenotype, osteogenic differentiation of VICs and AVC, thus accelerating the progression of CAVD.

Bioinspired polymeric heart valves: A combined in vitro and in silico approach

BackgroundPolymeric heart valves (PHVs) may address the limitations of mechanical and tissue valves in the treatment of valvular heart disease. In this study, a bioinspired valve was designed, assessed in silico, and validated by an in vitro model to develop a valve with optimum function for pediatric applications. MethodsA bioinspired heart valve was created computationally with leaflet curvature derived from native valve anatomies. A valve diameter of 18 mm was chosen to approach sizes suitable for younger patients. Valves of different thicknesses were fabricated via dip-coating with siloxane-based polyurethane and tested in a pulse duplicator for their hydrodynamic function. The same valves were tested computationally using an arbitrary Lagrangian–Eulerian plus immersed solid approach, in which the fluid–structure interaction between the valves and fluid passing through them was studied and compared with experimental data. ResultsComputational analysis showed that valves of 110 to 200 μm thickness had effective orifice areas (EOAs) of 1.20 to 1.30 cm2, with thinner valves exhibiting larger openings. In vitro tests demonstrated that PHVs of similar thickness had EOAs of 1.05 to 1.35 cm2 and regurgitant fractions (RFs) <7%. Valves with thinner leaflets exhibited optimal systolic performance, whereas thicker valves had lower RFs. ConclusionsBioinspired PHVs demonstrated good hydrodynamic performance that exceeded ISO 5840-2 standards. Both methods of analysis showed similar correlations between leaflet thickness and valve systolic function. Further development of this PHV may lead to enhanced durability and thus a more reliable heart valve replacement than contemporary options.

Native-Valve Aspergillus Endocarditis: Case Report and Literature Review.

Aspergillus endocarditis represents the second etiological cause of prosthetic endocarditis following Candida spp. On the other hand, native-valve endocarditis due to Aspergillus are anecdotally reported with increasing numbers in the last decade due to new diagnostic technologies such as polymerase chain reaction (PCR) on samples like valve tissue or entire blood. We performed a review of the literature presenting one case report observed at Pisa University Hospital. Seventy-four case reports have been included in a period between 1950-2022. Immunocompromised status (patients with solid tumor/oncohematological cancer or transplanted patients) was confirmed to be the main risk factor for this rare opportunistic infection with a high rate of metastatic infection (above all, central nervous system) and mortality. Diagnosis relies on serum galactomannan and culture with PCR on valve tissue or whole blood. Cardiac surgery was revealed to be a life-saving priority as well as appropriate antifungal therapy including b-liposomal amphotericin or new triazoles (isavuconazole). The endocarditis team, facing negative blood culture endocarditis affecting an immunocompromised patient, should investigate this difficult-to-treat pathogen.

Targeted inhibition of PTPN22 is a novel approach to alleviate osteogenic responses in aortic valve interstitial cells and aortic valve lesions in mice

BackgroundCalcific aortic valve disease (CAVD) is the most prevalent valvular disease and has high morbidity and mortality. CAVD is characterized by complex pathophysiological processes, including inflammation-induced osteoblastic differentiation in aortic valve interstitial cells (AVICs). Novel anti-CAVD agents are urgently needed. Protein tyrosine phosphatase nonreceptor type 22 (PTPN22), an intracellular nonreceptor-like protein tyrosine phosphatase, is involved in several chronic inflammatory diseases, including rheumatoid arthritis and diabetes. However, it is unclear whether PTPN22 is involved in the pathogenesis of CAVD.MethodsWe obtained the aortic valve tissue from human and cultured AVICs from aortic valve. We established CAVD mice model by wire injury. Transcriptome sequencing, western bolt, qPCR, and immunofluorescence were performed to elucidate the molecular mechanisms.ResultsHere, we determined that PTPN22 expression was upregulated in calcific aortic valve tissue, AVICs treated with osteogenic medium, and a mouse model of CAVD. In vitro, overexpression of PTPN22 induced osteogenic responses, whereas siRNA-mediated PTPN22 knockdown abolished osteogenic responses and mitochondrial stress in the presence of osteogenic medium. In vivo, PTPN22 ablation ameliorated aortic valve lesions in a wire injury-induced CAVD mouse model, validating the pathogenic role of PTPN22 in CAVD. Additionally, we discovered a novel compound, 13-hydroxypiericidin A 10-O-α-D-glucose (1 → 6)-β-D-glucoside (S18), in a marine-derived Streptomyces strain that bound to PTPN22 with high affinity and acted as a novel inhibitor. Incubation with S18 suppressed osteogenic responses and mitochondrial stress in human AVICs induced by osteogenic medium. In mice with aortic valve injury, S18 administration markedly alleviated aortic valve lesions.ConclusionPTPN22 plays an essential role in the progression of CAVD, and inhibition of PTPN22 with S18 is a novel option for the further development of potent anti-CAVD drugs.Graphical Therapeutic inhibition of PTPN22 retards aortic valve calcification through modulating mitochondrial dysfunction in AVICs.

The Role of Poly-glycerol Sebacate/Gelatin Coating Layer on Biological Features and Calcification Rate of 3D Melt-Molded Antibacterial Scaffold for Heart Valve Tissue Engineering

The Role of Poly-glycerol Sebacate/Gelatin Coating Layer on Biological Features and Calcification Rate of 3D Melt-Molded Antibacterial Scaffold for Heart Valve Tissue Engineering

Decreased expression of RPL15 and RPL18 exacerbated the calcification of valve interstitial cells during aortic valve calcification.

Calcific aortic valve disease (CAVD)is the most common valvular heart disease, with an increasing prevalence due to an aging population. The pathobiology of CAVD is a multifaceted and actively regulated process, but the detailed mechanisms have not been elucidated. The present study aims to identify the differentially expressed genes (DEGs)in calcified aortic valve tissues, and to analyze the correlation between DEGs and clinical features in CAVD patients. The DEGs were screened by microarray in normal and CAVD groups (n = 2 for each group), and confirmed by quantitative real-time polymerase chain reaction in normal (n = 12) and calcified aortic valve tissues (n = 34). A total of 1048 DEGs were identified in calcified aortic valve tissues, including 227 upregulated mRNAs and 821 downregulated mRNAs. Based on multiple bioinformatic analyses, three 60S ribosomal subunit components (RPL15,RPL18, and RPL18A), and two 40S ribosomal subunit components (RPS15and RPS21) were identified as the top 5 hub genes in the protein-protein interaction network of DEGs. The expression of RPL15 and RPL18 was also found significantly decreased in calcified aortic valve tissues (both p < .01), and negatively correlated with the osteogenic differentiation marker OPN in CAVD patients (both p < .01). Moreover, inhibition of RPL15 or RPL18 exacerbated the calcification of valve interstitial cells under osteogenic induction conditions. The present study proved that decreased expression of RPL15 and RPL18 was closely associated with aortic valve calcification, which provided valuable clues to find therapeutic targets for CAVD.

Posterior annulus elevation using pledget stitch: An adjuvant technique to improve the mitral valve coaptation in pediatric mitral valve repair

Link of Video Abstract: https://www.youtube.com/watch?v=8PNO8KPQFTY Purpose: Achieving an optimal result in mitral valve repair can be challenging in children due to the delicate nature of the mitral valve tissue, a wide range of pathologies, and a high incidence of co-existing cardiac anomalies. This study aimed to evaluate a novel adjuvant technique, posterior annulus elevation using pledget stitch, to improve mitral valve coaptation in pediatric mitral valve repair. Patients and methods: A retrospective cohort study was conducted at the National Cardiovascular Center Harapan Kita. Patients with severe mitral regurgitation who underwent mitral valve repair with posterior annulus elevation using pledget stitch between January 2021 and October 2021 were included. Transesophageal echocardiography (TEE) at day-0 and transthoracic echocardiography (TTE) at day-5 and 3 months after surgery was performed to assess coaptation length and residual regurgitation. Results: Twelve patients were included in this study with a mean age of 13.13 ± 2.98 years. The mean coaptation length was 6.94 ± 1.44 mm immediately after surgery. At day 5, 11 patients exhibited no or only trivial regurgitation (91.67%), with a mean coaptation length of 7.18 ± 1.72 mm. During a three-month follow-up period, 10 patients had no or only trivial regurgitation (83.33%) with the rest only developing mild regurgitation (16.67%), with a mean coaptation length of 7.60 ± 1.41 mm. No mortality or adverse events related to the procedure were observed during the follow-up. Conclusion: Posterior annulus elevation using pledget stitch as a novel adjuvant technique during mitral valve repair showed promising results in improving leaflet coaptation in pediatric patients. This technique may provide an additional option for mitral valve repair when the conventional technique yields unsatisfactory results.

Functional differences in human aortic valve interstitial cells from patients with varying calcific aortic valve disease.

Calcific aortic valve disease (CAVD) is characterized by progressive stiffening of aortic valve (AV) tissues, inducing stenosis and insufficiency. Bicuspid aortic valve (BAV) is a common congenital defect in which the AV has two leaflets rather than three, with BAV patients developing CAVD decades years earlier than in the general population. Current treatment for CAVD remains surgical replacement with its continued durability problems, as there are no pharmaceutical therapies or other alternative treatments available. Before such therapeutic approaches can be developed, a deeper understanding of CAVD disease mechanisms is clearly required. It is known that AV interstitial cells (AVICs) maintain the AV extracellular matrix and are typically quiescent in the normal state, transitioning into an activated, myofibroblast-like state during periods of growth or disease. One proposed mechanism of CAVD is the subsequent transition of AVICs into an osteoblast-like phenotype. A sensitive indicator of AVIC phenotypic state is enhanced basal contractility (tonus), so that AVICs from diseased AV will exhibit a higher basal tonus level. The goals of the present study were thus to assess the hypothesis that different human CAVD states lead to different biophysical AVIC states. To accomplish this, we characterized AVIC basal tonus behaviors from diseased human AV tissues embedded in 3D hydrogels. Established methods were utilized to track AVIC-induced gel displacements and shape changes after the application of Cytochalasin D (an actin polymerization inhibitor) to depolymerize the AVIC stress fibers. Results indicated that human diseased AVICs from the non-calcified region of TAVs were significantly more activated than AVICs from the corresponding calcified region. In addition, AVICs from the raphe region of BAVs were more activated than from the non-raphe region. Interestingly, we observed significantly greater basal tonus levels in females compared to males. Furthermore, the overall AVIC shape changes after Cytochalasin suggested that AVICs from TAVs and BAVs develop different stress fiber architectures. These findings are the first evidence of sex-specific differences in basal tonus state in human AVICs in varying disease states. Future studies are underway to quantify stress fiber mechanical behaviors to further elucidate CAVD disease mechanisms.

Multimodality Imaging of Aortic Valve Calcification and Function in a Murine Model of Calcific Aortic Valve Disease and Bicuspid Aortic Valve.

Calcific aortic valve disease (CAVD) is a prevailing disease with increasing occurrence and no known medical therapy. Dcbld2-/- mice have a high prevalence of bicuspid aortic valve (BAV), spontaneous aortic valve calcification, and aortic stenosis (AS). 18F-NaF PET/CT can detect the aortic valve calcification process in humans. However, its feasibility in preclinical models of CAVD remains to be determined. Here, we sought to validate 18F-NaF PET/CT for tracking murine aortic valve calcification and leveraged it to examine the development of calcification with aging and its interdependence with BAV and AS in Dcbld2-/- mice. Methods: Dcbld2-/- mice at 3-4 mo, 10-16 mo, and 18-24 mo underwent echocardiography, 18F-NaF PET/CT (n = 34, or autoradiography (n = 45)), and tissue analysis. A subset of mice underwent both PET/CT and autoradiography (n = 12). The aortic valve signal was quantified as SUVmax on PET/CT and as percentage injected dose per square centimeter on autoradiography. The valve tissue sections were analyzed by microscopy to identify tricuspid and bicuspid aortic valves. Results: The aortic valve 18F-NaF signal on PET/CT was significantly higher at 18-24 mo (P < 0.0001) and 10-16 mo (P < 0.05) than at 3-4 mo. Additionally, at 18-24 mo BAV had a higher 18F-NaF signal than tricuspid aortic valves (P < 0.05). These findings were confirmed by autoradiography, with BAV having significantly higher 18F-NaF uptake in each age group. A significant correlation between PET and autoradiography data (Pearson r = 0.79, P < 0.01) established the accuracy of PET quantification. The rate of calcification with aging was significantly faster for BAV (P < 0.05). Transaortic valve flow velocity was significantly higher in animals with BAV at all ages. Finally, there was a significant correlation between transaortic valve flow velocity and aortic valve calcification by both PET/CT (r = 0.55, P < 0.001) and autoradiography (r = 0.45, P < 0.01). Conclusion: 18F-NaF PET/CT links valvular calcification to BAV and aging in Dcbld2-/- mice and suggests that AS may promote calcification. In addition to addressing the pathobiology of valvular calcification, 18F-NaF PET/CT may be a valuable tool for evaluation of emerging therapeutic interventions in CAVD.

Complete Genome Sequence of Legionella cardiaca Strain H63T, Isolated from a Case of Native Valve Endocarditis.

We report the complete genome sequence of Legionella cardiaca strain H63T, which had been isolated from aortic valve tissue from a patient with native endocarditis. The genome assembly contains a single 3,477,232-bp contig, with a G+C content of 38.59%, and is predicted to encode 2,948 proteins.

Past, present, and future options for right ventricular outflow tract reconstruction.

The pulmonary valve is the most frequently replaced cardiac valve in congenital heart diseases. Whether the valve alone or part of the right ventricular outflow tract have to be repaired or replaced depends on the specific pathological anatomy of the malformation. Once the decision to replace the pulmonary valve has been made, two options are available: the isolated transcatheter pulmonary valve replacement and the surgical implantation of a prosthetic valve either isolated or in combination with a procedure on the right ventricular outflow tract. In this paper, we will focus on the different past and present surgical options and present a new concept called "endogenous tissue restoration," a promising alternative to the hitherto existing implants. From a general point of view, neither the transcatheter nor the surgical valvular implants are magic bullets in the arsenal for the management of valvular diseases. Smaller valves have to be frequently replaced because of outgrowth of the patients, larger tissue valves may present late structural valve deterioration, while xenograft and homograft conduits may calcify and therefore become narrowed within unpredictable incidence and interval following implantation. Based on long-term research efforts combining the knowledge of supramolecular chemistry, electrospinning, and regenerative medicine, endogenous tissue restoration has emerged most recently as a promising option to create long-term functioning implants. This technology is appealing because following resorption of the polymer scaffold and timely replacement through autologous tissue, no foreign material remain at all in the cardiovascular system. Proof-of-concept studies as well as small first-in-man series have been completed and have demonstrated favorable anatomic and hemodynamic results, comparable to currently available implants in the short term. Based on the initial experience, important modifications to improve the pulmonary valve function have been initiated.

BIO3: Advancement of a Novel Polymeric Transcatheter Aortic Valve as an Alternative to Tissue-based Valves

Background: Transcatheter aortic valve replacement (TAVR) is a minimally invasive alternative to surgical valve replacement, originally targeted to elderly patients with aortic stenosis (AS), now increasingly utilized in younger lower risk AS patients. With growth of TAVR the shortcomings of current tissue-based valves are becoming prevalent, namely limited durability and thromboembolic risk. To address these, a polymeric TAV named PolyV-2 (27 mm, PolyNova Cardiovascular Inc, Stony Brook, NY) was designed, optimized, and further tested. Methods: The design of the PolyV-2 (Figure A) was achieved with a battery of in silico simulations including the use of finite element analysis (FEA, Abaqus 2020, Dassault Systems, Providence, RI) to optimize the radial force of the stent frame and minimize leaflet stresses during the cardiac cycle. The PolyV-2 employs a sutureless design via coating the stent with polymer, bypassing problematic hand suturing manufacture of tissue valves. The PolyV-2 utilizes a thermoplastic elastomer polymeric material which was tested in vitro with accelerated wear durability testing according to ISO 5840-3 (2015) with periodic performance testing, evaluated against tissue-based surgical and TAV devices for platelet activation rate (PAR) in a pulsatile flow loop, and evaluated for calcification risk with similar wear testing in a pro-calcific medium. To assess the deposition of calcifications in the valves, both µCT and ICP spectroscopy were used. Results: The optimization process of the PolyV-2 leaflets (Figure B) was able to greatly lower the peak and mean stresses throughout over the cardiac cycle by employing a variable thickness across the entire leaflet. With success of this in silico optimization process, the leaflets were then tested in vitro (Figure C) in accelerated wear testing, performing 1Billion cycles w/o failure – correlating to 25 years of efficacy in vivo, exceeding the 250 million minimum required by the FDA. The material also demonstrated favorable hemocompatiblity as to PAR (Figure D) with activation significantly lower than a commercial tissue TAVR device, more comparable to a surgical device. The pro-calcific wear testing demonstrated no deposition of calcific salts within the polymer leaflet (µCT image, Figure E) compared to the tissue valve and minimal calcium detected with ICP spectroscopy. Conclusion: To mitigate the persistent complications of tissue-based TAV devices, the polymeric PolyV-2 valve was optimized through a battery of in silico and in vitro trials to offer superior hemodynamics, performance, and durability. Proper design and material considerations are essential to ensure successful translation, demonstration of enhanced bio/hemocompatibility and advance of the PolyV-2 through in vivo animal trials.

Association of citrullination with the progression of aortic stenosis

Despite its clinical importance, biomarkers of disease activity in aortic stenosis (AS) are lacking. We investigated the association between anti-cyclic citrullinated peptide (CCP) antibodies and AS. All 678 patients who underwent echocardiography and anti-CCP antibody testing were analysed. Anti-CCP antibody status was categorized as negative, low-positive, and high-positive. In addition, aortic valve (AV) tissues were obtained from the patients with and without AS to analyze the presence of citrullinated proteins. At baseline, 241 (35.5%) subjects with AV degeneration had a higher rate of anti-CCP antibody positivity (42.7% versus 34.6%, p = 0.035) than those without AV degeneration. Out of the 331 (48.8%) subjects who underwent echocardiographic follow-up, progression of AS was observed in 34 (10.3%) patients, with a higher incidence in the high-positive group compared to the low-positive or negative group (19.0% vs. 11.3% vs. 8.4%, respectively; p = 0.041). On multivariable analysis, high anti-CCP antibody positivity was independently associated with progression to AS (odds ratio: 2.312; 95% confidence interval: 1.006–5.310; p = 0.048). Furthermore, immunohistochemistry and Western blotting revealed increased citrullination in diseased AV compared to normal AV tissue. This study demonstrated that a high positive anti-CCP antibody result is associated with AV degeneration and may be an independent factor for AS progression.

Effects of food, fasting, and exercise on plasma pyrophosphate levels and ENPP1 activity in healthy adults.

Inorganic pyrophosphate (PPi) is highly regulated as it plays a critical role in the regulation of physiological mineralization. Dysregulation of plasma PPi is associated with skeletal hypomineralization and pathogenic mineralization in soft connective tissue, arteries, and heart valves. There is no standard approach to measuring PPi, making it difficult to establish PPi as a biomarker of mineralization disorders. This study aims to determine the impact of time of day, meals, or exercise on plasma PPi homeostasis using a highly sensitive PPi assay. In this single-center trial, a clinical laboratory improvement amendment (CLIA) validated modified sulfurylase-based adenosine 5-triphosphate (ATP) assay was used to measure PPi levels throughout the day in 10 healthy adults under 3 conditions; normal diet (non-fasting), fasting, and normal diet with exercise. Serum ectonucleotide pyrophosphatase/phosphodiesterase 1 activity (ENPP1; an enzyme that produces PPi) was also measured to determine whether these conditions influence PPi levels through ENPP1 activity. There is a circadian increase in mean PPi levels under fasting and non-fasting conditions between 8am and 6pm, followed by a rapid return to baseline overnight. A circadian increase in ENPP1 activity was also measured under fasting but was lost under non-fasting conditions. Meals increased the individual variability of PPi levels when compared to the same individual fasting. PPi levels and ENPP1 activity exhibited a short-term increase after intense exercise. We found PPi ranges from 1465nM to 2969nM (mean 2164nM) after fasting overnight. Within this range, there was lower intra-subject variability in PPi, suggesting that each individual has a uniquely regulated normal PPi range. Plasma levels of PPi can be reliably measured after an overnight fast and show promise as a biomarker of mineralization disorders.