Stenotic Valve Research Articles

The new insight into extracellular NAD+ degradation-the contribution of CD38 and CD73 in calcific aortic valve disease.

Nicotinamide adenine dinucleotide (NAD+) is crucial for cell energy metabolism and many signalling processes. Recently, we proved the role of ecto‐enzymes in controlling adenine nucleotide–dependent pathways during calcific aortic valve disease (CAVD). This study aimed to investigate extracellular hydrolysis of NAD+ and mononucleotide nicotinamide (NMN) in aortic valves and aorta fragments of CAVD patients and on the inner aortic surface of ecto‐5′‐nucleotidase knockout mice (CD73−/−). Human non‐stenotic valves (n = 10) actively converted NAD+ and NMN via both CD73 and NAD+‐glycohydrolase (CD38) according to our analysis with RP‐HPLC and immunofluorescence. In stenotic valves (n = 50), due to reduced CD73 activity, NAD+ was degraded predominantly by CD38 and additionally by ALP and eNPP1. CAVD patients had significantly higher hydrolytic rates of NAD+ (0.81 ± 0.07 vs 0.56 ± 0.10) and NMN (1.12 ± 0.10 vs 0.71 ± 0.08 nmol/min/cm2) compared with controls. CD38 was also primarily engaged in human vascular NAD+ metabolism. Studies using specific ecto‐enzyme inhibitors and CD73−/− mice confirmed that CD73 is not the only enzyme involved in NAD+ and NMN hydrolysis and that CD38 had a significant contribution to these pathways. Modifications of extracellular NAD+ and NMN metabolism in aortic valve cells may be particularly important in valve pathology and could be a potential therapeutic target.

Prosthetic Valve Monitoring via In Situ Pressure Sensors: In Silico Concept Evaluation using Supervised Learning.

Patients receiving transcatheter aortic valve replacement (TAVR) can benefit from continuous, longitudinal monitoring of valve prosthesis to prevent leaflet thrombosis-related complications. We present a computational proof-of-concept study of a novel, non-invasive and non-toxic valve monitoring technique for TAVs which uses pressure measurements from microsensors embedded on the valve stent. We perform a data-driven analysis to determine the signal processing and machine learning required to detect reduced mobility in individual leaflets. We use direct numerical simulations to describe hemodynamic differences in transvalvular flow in ascending aorta models with healthy and stenotic valves. A Cartesian-grid flow solver and a reduced-order valve model simulate the complex dynamics of blood flow and leaflet motion, respectively. The two-way fluid-structure interaction coupling is achieved using a sharp interface immersed boundary method. From a dataset of 21 simulations, we show leaflets with reduced mobility result in large, asymmetric pressure fluctuations in their vicinity, particularly in the region extending from the aortic sinus to the sino-tubular junction (STJ). We train a linear classifier algorithm by correlating sinus and STJ pressure measurements on the stent surface to individual leaflet status. The algorithm was shown to have >90% accuracy for prospective detection of individual leaflet dysfunction. We demonstrate that using only two discrete pressure measurements, per leaflet, on the TAV stent, individual leaflet status can be accurately predicted. Such a sensorized TAV system could enable safe and inexpensive detection of prosthetic valve dysfunction.

Histopathological Characterization of Mitral Valvular Lesions from Patients with Rheumatic Heart Disease.

ResumoFundamentos:Os mecanismos subjacentes pelos quais a doença cardíaca reumática (DCR) levam à disfunção valvar grave não são totalmente compreendidos.Objetivo:O presente estudo avaliou as alterações histopatológicas nas valvas mitrais (VM) buscando uma associação entre o padrão de disfunção valvar predominante e os achados histopatológicos.Métodos:Em 40 pacientes submetidos à troca da VM devido a DCR e em 20 controles submetidos a transplante cardíaco, foram analisados os aspectos histológicos da VM excisada. Dados clínicos e ecocardiográficos também foram coletados. As análises histológicas foram realizadas usando coloração com hematoxilina-eosina. Determinou-se inflamação, fibrose, neoangiogênese, calcificação e metaplasia adiposa. Valores de p<0,05 foram considerados estatisticamente significativos.Resultados:A idade média dos pacientes com DCR foi de 53±13 anos, sendo 36 (90%) do sexo feminino, enquanto a idade média dos controles foi de 50±12 anos, semelhante aos casos, sendo a maioria do sexo masculino (70%). O endocárdio valvar reumático apresentou espessura maior que os controles (1,3±0,5 mm versus 0,90±0,4 mm, p=0,003, respectivamente), e infiltrado inflamatório mais intenso no endocárdio (78% versus 36%; p=0,004), com predominância de células mononucleares. Ocorreu fibrose moderada a acentuada mais frequentemente em válvulas reumáticas do que em válvulas controle (100% vs. 29%; p<0,001). Ocorreu calcificação em 35% das valvas reumáticas, principalmente entre as valvas estenóticas, associada à área valvar mitral (p=0,003).Conclusões:Apesar do intenso grau de fibrose, o processo inflamatório permanece ativo na valva mitral reumática, mesmo em doença tardia com disfunção valvar. A calcificação predominou em valvas estenóticas e em pacientes com disfunção ventricular direita.

Model-based aortic power transfer: A potential measure for quantifying aortic stenosis severity based on measured data

Current aortic stenosis severity grading is based mainly on the local properties of the stenotic valve, such as pressure gradient or jet velocity. Success rates of valve replacement therapy are still suboptimal, so alternative grading of AS should be investigated. We suggest the efficiency of power transfer from the left ventricle to the aorta, as it takes into account heart, valve and circulatory system. Left ventricular and circulatory power were estimated using a 0D model, which was optimised to patient data: left ventricular and aortic pressure, aortic flow and diastolic left ventricular volume. Optimisation was performed using a data assimilation method. These data were available in rest as well as chemically induced exercise for twelve patients. Using this limited data set, we showed that aortic valve efficiency is highly heterogeneous between patients, but also often dependent on the haemodynamic load. This indicates that power transfer efficiency is a highly interesting metric for further research in aortic stenosis.

Implantation of a Sutureless Valve Into a Surgically Enlarged Aortic Root: A Bailout Option

Sutureless bioprostheses such as the Sorin Perceval Valve (SPV; Sorin Group, Srl, Saluggia, Italy) have been proposed for replacing stenotic native valves within small aortic roots of geriatric patients with significant comorbidity. Their use seems as safe as that of stented bioprostheses and enables significantly reduced length of surgery. Low transprosthetic pressure gradients have been measured. Because of the radial force of its self-expandable nitinol stent, aortic annulus interruption could be a relative contraindication to SPV use. Off-label implantation of the SPV into a surgically enlarged ascending aorta was first reported in this study, as a bailout option in the presence of a tiny aortic root.

Investigating Aortic Valve Calcification via Isolation and Culture of T Lymphocytes using Feeder Cells from Irradiated Buffy Coat.

Calcific aortic valve disease (CAVD), an active disease process ranging from mild thickening of the valve to severe calcification, is associated with high mortality, despite new therapeutic options such as transcatheter aortic valve replacement (TAVR). The complete pathways that start with valve calcification and lead to severe aortic stenosis remain only partly understood. By providing a close representation of the aortic valve cells in vivo, the assaying of T lymphocytes from stenotic valve tissue could be an efficient way to clarify their role in the development of calcification. After surgical excision, the fresh aortic valve sample is dissected in small pieces and the T lymphocytes are cultured, cloned then analyzed using fluorescence activated cell sorting (FACS). The staining procedure is simple and the stained tubes can also be fixed using 0.5% of paraformaldehyde and analyzed up to 15 days later. The results generated from the staining panel can be used to track changes in T cell concentrations over time in relation to intervention and could easily be further developed to assess activation states of specific T cell subtypes of interest. In this study, we show the isolation of T cells, performed on fresh calcified aortic valve samples and the steps of analyzing T cell clones using flow cytometry to further understand the role of adaptive immunity in CAVD pathophysiology.

H-repair in supravalvular aortic stenosis.

H-repair in supravalvular aortic stenosis.

Non-Invasive Evaluation of Systemic Vascular Load in Patients With Aortic Stenosis Before and After Transcatheter Aortic Valve Replacement

In patients with aortic stenosis (AS), the contribution of systemic arterial load to left ventricular afterload may be masked by the stenotic valve. We aimed to evaluate the potential of using combined cardiac magnetic resonance (CMR) and applanation tonometry (AT) to assess changes in systemic arterial load in AS patients before and after transcatheter aortic valve replacement (TAVR).

Current Advances in Transcatheter Intervention for Children Born with Congenital Heart Defects: A Review of Literature

This review aims to sum up the improvements witnessed in the field of interventional cardiology during recent times. The last decade has witnessed significant technical advances in the field of radiological imaging and also in interventional cardiology which has helped to offer more non-invasive solutions for the management of congenital heart defects. This has resulted from the use of advanced 3-dimensional fusion imaging instead of conventional 2-dimensional angiography, applying interactive real-time enhancement and using computed tomography and Magnetic Resonance Imaging for interventional procedures. Similarly the introduction of next generation devices, have not only improved the final outcome of the procedure but also has helped in reducing the challenges that were faced before and with the initial generation of devices. These advances have helped not only in reducing the radiation exposure, the use of contrast medium dose but also have resulted in improved early survival. The field of neonatal cardiology has advanced at an unprecedented pace. The transcatheter closure of patent ductus arteriosus has evolved over time and now it has been made possible at much lower body weight. Similarly, early use of stents for aortic coarctation has been found effective in some patients, especially when surgical intervention had been denied. The application of the hybrid approach for the management of complex congenital heart defects has also been effectively applied. More recently transcatheter placement of the pulmonary valve has been introduced for severely stenotic and/or regurgitant pulmonary valve in adolescents and adults. It is anticipated that in near future, this procedure would be available for relatively younger patients. In conclusion: last 2 decades have improvised pediatric interventional cardiology to incorporate less invasive solutions for CHD. The current advances in radio-diagnostic imaging, gadgetry and technical expertise have improved significantly and led to manage many of such defects by trans-catheter approach. This has led also, to replace the early surgical intervention with a more subtle hybrid approach, thus reducing not only the major surgical trauma but also been found to be cost-effective due to a shorter hospital stay. But a learning curve for performers is required for optimum results and also such procedures should be performed in a fully developed facility with an optimum surgical backup.

Unusual Cause of Left Ventricular Pseudoaneurysm

Closed mitral valvotomy (CMV) became an accepted surgical procedure to open a stenotic mitral valve (MV) about 50 years ago. CMV is performed through an incision in the left atrial appendage. Tubbs dilator is passed in to the left ventricle via the apex and then advanced retrogradely through the stenosed MV and is then opened within the orifice to split the commissures. The dilator is then removed and the orifice closed. Incisional left ventricular pseudo aneurysm has been described as a rare complication of this technique. Here we encountered a similar scenario. Percutaneous transmitral commissurotomy has virtually replaced CMV. But with the expanding use of the transapical approach to treat a variety of structural heart diseases, especially transcutaneous aortic valve replacement, one is likely to encounter similar complications in the modern era also.

Left atrial volume, predictive factor of the reduction of global longitudinal strain in hypertensive patients with preserved left ventricular ejection fraction

Dilatation of the left atrium (LA) is usually found in high blood pressure without any valve damage. This dilatation is one of the prognostic markers and may be a reflection of left ventricular diastolic dysfunction. It can be used as one of the factors of morbi cardiovascular mortality. Diastolic dysfunction is acknowledged to be the predominant pathophysiological mechanism in patients with heart failure with preserved ejection fraction. This work consists in carrying out in a series of 200 hypertensive patients (aged 25 to 75 years) an echocardiographic study, including the LVEF, the calculation of the indexed left ventricular mass as well as the relative parietal thickness, the calculation of the volume of the left atrium and the analysis of the diastolic function and finally the study of the longitudinal deformation of the LV. Excluded from this study were patients with secondary hypertension, leaky or stenotic valve disease, arrhythmia, history of coronary insufficiency. Of the 200 hypertensive patients, 28 patients had a high LA volume, of which 27 patients had high filling pressures. Of the 28 patients with high LA volume 18 patients (64.2%) had low GLS. Patients with high LA volume are twice as likely to have low GLS as other patients. There is a statistically very significant relationship between lower GLS, increased left atrium volume, and increased left ventricular filling pressures in hypertensive patients. These results suggest that the increase in filling pressures is closely associated with atrioventricular interaction in patients with hypertension, with a perfect correlation with achievement of longitudinal systolic and diastolic dysfunction (Table 1). The evaluation of LA size and function provides a powerful and dynamic morphophysiological marker of cardiovascular disease status that can be used longitudinally to quantify the extent of structural and functional remodeling.

Parachute Mitral Valve: Anatomy and Operation.

Parachute mitral valve is a rare congenital heart defect characterised by a distorted mitral geometry with a single papillary muscle for all mitral chords to attach. It may develop in isolation or as a constillation of Shone syndrome. By comprehensive retrieval of the pertinent articles published since 2000, 22 articles with 149 cases of parachute mitral valve were recruited into this study. The present article revealed that most patients with a parachute mitral valve had a stenotic or regurgitant mitral valve, which is often associated with left heart obstructions, thereby leading to haemodynamic compromise. Therefore, multiple surgical maneuvers are warranted for such patients. Mitral valve repair is preferred over mitral valve replacement for the mitral valveabnormalities so as to avoid the associated complications of valve replacement procedure. The patients' outcomes are satisfactory with a total event-free survival of surgical patients of 84.8%. Key Words: Cardiac surgical procedures, Congenital heart defects, Mitral valve.

S2307 COVID-19 in a Patient on Dual Biologic Therapy for Inflammatory Bowel Disease

INTRODUCTION: Preliminary data suggest that dual biologic therapy might be effective and safe in a subgroup of inflammatory bowel disease (IBD) patients. However, the safety and outcomes of dual biologic therapy in IBD with Coronavirus Disease 19 (COVID-19) is unknown. Here, we present a case of a Crohn’s disease (CD) patient on adalimumab (ADA) and ustekinumab (UST) combination therapy who developed COVID-19. CASE DESCRIPTION/METHODS: This is a 24-year-old man with fibrostenotic Crohn’s ileocolitis diagnosed at age 9. He had a secondary loss of response to infliximab despite dose escalation to 10 mg/kg in combination with methotrexate (MTX). He was then transitioned to ADA and dose was escalated to 40 mg weekly with MTX (subsequently self-discontinued MTX). He achieved clinical response but not remission with ADA. Magnetic resonance enterography showed active inflammation in the terminal ileum, distal sigmoid colon, and rectum (Image 1). A colonoscopy showed ulcerated and polypoid mucosa in the terminal ileum and at the ileocecal valve with narrowing and patchy, mild pan-colonic inflammation (Image 2A/B). ADA level was 17 mcg/mL without antibodies. Switching to a different biologic was recommended. The patient was hesitant about discontinuing ADA due to symptomatic improvement. After discussion of risks and benefits, it was decided to bridge with UST and continue ADA with a plan to eventually discontinue ADA if remission was achieved. He received standard intravenous UST loading followed by 90 mg subcutaneously every 8 weeks. Five months later, he tested positive for COVID-19 due to exposure to an infected individual. He was asymptomatic from a respiratory standpoint and his gastrointestinal (GI) symptoms were at baseline. He received a dose of UST 1 day prior to COVID-19 testing and last ADA was 1 week prior to testing. ADA was held and resumed 2 weeks after as he remained without fever, respiratory symptoms or new onset GI symptoms at 2 and 6 weeks after testing positive for COVID-19. DISCUSSION: This case describes a favorable outcome of a CD patient who tested positive for COVID-19 while on ADA and UST. Multiple series have demonstrated that biologic monotherapy is not associated with poor outcomes in COVID-19 infected IBD patients. Instead, corticosteroids, advanced age and co-morbidities are predictors of adverse outcomes. However, more data is needed on the safety of combination biologic therapy in the COVID-19 era.Image 1.: Magnetic resonance enterography (coronal T1 weighted image) showing wall thickening, edema and hyperenhancement involving the terminal ileum over a length of approximately 20 cm with associated vascular engorgement is present.Image 2.: Colonoscopy images showing polypoid stenotic ileoceal valve (A) and the terminal ileum showing ulcerations (B).

Uncertainty in model-based treatment decision support: Applied to aortic valve stenosis.

Patient outcome in trans‐aortic valve implantation (TAVI) therapy partly relies on a patient's haemodynamic properties that cannot be determined from current diagnostic methods alone. In this study, we predict changes in haemodynamic parameters (as a part of patient outcome) after valve replacement treatment in aortic stenosis patients. A framework to incorporate uncertainty in patient‐specific model predictions for decision support is presented. A 0D lumped parameter model including the left ventricle, a stenotic valve and systemic circulatory system has been developed, based on models published earlier. The unscented Kalman filter (UKF) is used to optimize model input parameters to fit measured data pre‐intervention. After optimization, the valve treatment is simulated by significantly reducing valve resistance. Uncertain model parameters are then propagated using a polynomial chaos expansion approach. To test the proposed framework, three in silico test cases are developed with clinically feasible measurements. Quality and availability of simulated measured patient data are decreased in each case. The UKF approach is compared to a Monte Carlo Markov Chain (MCMC) approach, a well‐known approach in modelling predictions with uncertainty. Both methods show increased confidence intervals as measurement quality decreases. By considering three in silico test‐cases we were able to show that the proposed framework is able to incorporate optimization uncertainty in model predictions and is faster and the MCMC approach, although it is more sensitive to noise in flow measurements. To conclude, this work shows that the proposed framework is ready to be applied to real patient data.

Development of Tissue Engineered Heart Valves for Percutaneous Transcatheter Delivery in a Fetal Ovine Model

This multidisciplinary work shows the feasibility of replacing the fetal pulmonary valve with a percutaneous, transcatheter, fully biodegradable tissue-engineered heart valve (TEHV), which was studied invitro through accelerated degradation, mechanical, and hemodynamic testing and invivo by implantation into a fetal lamb. The TEHV exhibited only trivial stenosis and regurgitation invitro and no stenosis invivo by echocardiogram. Following implantation, the fetus matured and was delivered at term. Replacing a stenotic fetal valve with a functional TEHV has the potential to interrupt the development of single-ventricle heart disease by restoring proper flow through the heart.

Cyclophilin A inhibition as potential treatment of human aortic valve calcification

Aortic valve stenosis (AS) is a pathological condition that affects about 3% of the population, representing the most common valve disease. The main clinical feature of AS is represented by the impaired leaflet motility, due to calcification, which leads to the left ventricular outflow tract obstruction during systole. The formation and accumulation of calcium nodules are driven by valve interstitial cells (VICs). Unfortunately, to date, the in vitro and in vivo studies were not sufficient to fully recapitulate all the pathological pathways involved in AS development, as well as to define a specific and effective pharmacological treatment for AS patients.Cyclophilin A (CyPA), the most important immunophilin and endogenous ligand of cyclosporine A (CsA), is strongly involved in several detrimental cardiovascular processes, such as calcification. To date, there are no data on the CyPA role in VIC-mediated calcification process of AS. Here, we aimed to identify the role of CyPA in AS by studying VIC calcification, in vitro.In this study, we found that (i) CyPA is up-regulated in stenotic valves of AS patients, (ii) pro-calcifying medium promotes CyPA secretion by VICs, (iii) in vitro treatment of VICs with exogenous CyPA strongly stimulates calcium deposition, and (iv) exogenous CyPA inhibition mediated by CsA analogue MM284 abolished in vitro calcium potential. Thus, CyPA represents a biological target that may act as a novel candidate in the detrimental AS development and its inhibition may provide a novel pharmacological approach for AS treatment.

Effects of rivaroxaban and dabigatran on local expression of coagulation and inflammatory factors within human aortic stenotic valves

BackgroundTreatment with non-vitamin K antagonist oral anticoagulants (NOACs) such as dabigatran (a direct thrombin inhibitor) or rivaroxaban (a direct inhibitor of factor [F] Xa) attenuates atherosclerotic plaque progression in hypercholesterolemic mice.Purpose: To evaluate the effect of NOACs application on the expression of coagulation proteins in loco within stenotic aortic valves and in valve interstitial cells (VICs) from patients with severe aortic stenosis (AS). MethodsPrimary cultures of VICs obtained from 90 patients undergoing aortic valve replacement were stimulated with TNF-α (50 ng/mL) and pre-treated with rivaroxaban (1 and 10 ng/mL) or dabigatran (25 and 250 ng/mL). The expression of coagulation proteins was analyzed by immunofluorescence. Cytokine levels were measured by ELISA.Results: FX, FXa, FVII, thrombin and PAR1/2 were present in loco within human aortic stenotic valves. Cultured VICs exhibited constant expression of FX, TF, PAR1/2. Exposure of VICs to TNF-α caused the upregulated expression of TF, PAR1/2 and induced expression of thrombin, FVII and FXa. FX was expressed by 80% of VICs, regardless of stimulation. Cultured VICs were able to synthesize metalloproteinases 1–3, IL-6, IL-32, IL-34, osteopontin and osteocalcin, the levels of which increased under TNF-α stimulation. NOACs added to culture inhibited coagulation factor and PAR1/2 expression. Moreover, NOACs down-regulated VIC-derived proteins responsible for valve calcification and extracellular matrix remodeling. ConclusionsNOACs at therapeutic concentrations may inhibit the effects of FXa and thrombin at in vitro level. It might be speculated that long-term treatment with rivaroxaban or dabigatran could attenuate the progression of AS in humans.

3D-printed stenotic aortic valve model to simulate physiology before, during, and after transcatheter aortic valve implantation

AimsPressure loss versus transvalvular flow analysis challenges physiologic models of current aortic valve stenosis. New conceptual frameworks are needed to explain these real-world observations. Methods and resultsA patient-specific, 3D-printed, silicon model of a stenotic valve was placed inside an in-vitro haemodynamic model of the circulatory system. Instantaneous pressure and flow in the aorta and left ventricle were simulated according to measured patient specific parameters. Thereafter, a realistic transcatheter aortic valve was implanted (TAVI) in the model. Simulated post-TAVI mean pressure gradients resembled patient observations (3.7 ± 0.7 mmHg vs 6.7 ± 2.3 mmHg), but pre-TAVI measurements underestimated the pressure gradient (35.1 ± 0.6 mmHg vs 45.3 ± 1.5 mmHg). ConclusionPatient-specific 3D-printed stenotic aortic valve models could simulate baseline haemodynamics. A TAVI procedure was successfully performed on the 3D silicone rubber valve in a physiologic in-vitro model. Pre-TAVI haemodynamics in the model underestimated in-patient mean pressure gradient, whereas post TAVI pressure gradient was predicted correctly with the TAVI valve inside the 3D printed model. This study shows that these types of models could be used to study AS hemodynamics with the TAVI valve inside the 3D printed model. Improvements in the 3D-printed model, like addition of calcification and fine-tuning of the haemodynamic model, could further enhance accuracy of the simulation.

Mitral valve replacement in mitral stenosis; the problem of small left ventricle

BackgroundMitral valve stenosis in adults especially due to rheumatic heart disease may be associated with a smaller than normal left ventricular cavity. Mitral valve replacement in such cases may lead to hemodynamic instability either during weaning from cardiopulmonary bypass or in the early postoperative period manifested by the need for inotropic support and even mortality due to low cardiac output syndrome.Patients and methods184 patients with predominately severe stenotic mitral valves who underwent elective isolated mitral valve replacement in the period between January 2012 and January 2018 at our hospital were included in this study. Patients were divided into 2 matched groups; (small LV group) consisting of 86 cases and (normal or dilated LV group) consisting of 98 cases.ResultsThere were no statistically significant differences in operative details among both groups apart from the need for inotropic support and intra-aortic balloon pump due to low cardiac output which were statistically significantly higher in (small LV group) than (normal or dilated LV group) with a p-values of 0.01 and 0.03 respectively. Within the ICU stay only the incidence of occurrence of heart failure was significantly higher in (small LV group) with a p-value of 0.008. No statistically significant difference could be elicited in the in-hospital mortality between both groups (p-value = 0.1).ConclusionPatients with mitral valve stenosis and small left ventricular cavity are in a higher need for inotropic and even mechanical support after mitral valve replacement as well as at a higher risk for the development of heart failure before hospital discharge than patients with mitral stenosis and normal-sized left ventricular cavity.

Desaturation and hypotension in a dog undergoing balloon valvuloplasty for pulmonic stenosis

A 4-year old male miniature schnauzer with severe pulmonic stenosis was presented for percutaneous balloon valvuloplasty. The dog had been managed medically with atenolol for a month prior to the...