Stenotic Valve Research Articles

DOES LV EF IMPROVE 1 YEAR FOLLOWING SUCCESSFUL TAVR? IMPACT OF GENDER, REMODELING, AND TOTAL ARTERIAL LOAD

Left ventricular remodeling and systolic function in aortic stenosis results in concentric hypertrophy pattern which mitigates the increased systolic load caused by the stenotic valve. SAVR have shown that AVR results in a decline in afterload and a commensurate improvement in EF. The situation in

Ciężkie zwężenie zastawki aortalnej u noworodka

Aortic stenosis is a congenital heart disease which may present with different symptomatology and may lead to heart failure in newborn. A case of a 9-days old newborn with a severe aortic stenosis is presented. Due to impaired systolic function of the left ventricle and rapidly increasing symptoms of heart failure (tachypnea, dyspnoea, tachycardia) the neonate required pharmacological treatment (prostaglandin E1 infusion and phosphodiesterase inhibitor c-AMP) and balloon valvuloplasty as a matter of urgency. In chest X-ray the heart silhouette was enlarged, the electrocardiogram showed signs of overload of both ventricles. In echocardiography thickened aortic valves with a pin-hole opening, normal left ventricle size with signs of its hypertrophy and reduced contractility (ejection fraction 45%) and a moderate mitral regurgitation were found. Angiography and balloon valvuloplasty of the aortic valve was performed through puncture of the right femoral artery. After expansion of the balloon at the stenotic valve a very good result of the treatment was achieved – low invasive gradient (22 mm Hg) between the left ventricle and the aorta and a trivial aortic valve regurgitation. The good outcome of the procedure was confirmed and monitored in the next days. The general state of the child improved significantly, systolic function of the left ventricle returned to normal values. Because of a complication after the procedure – a thrombosis in the external iliac artery, a 3-month anti-clotting therapy was performed. No improvement in the patency of the vessel was observed; however, abundant collateral vessels provided the extremity with proper circulation.

Investigation of phase-contrast magnetic resonance imaging underestimation of turbulent flow through the aortic valve phantom: experimental and computational study using lattice Boltzmann method.

The accuracy of phase-contrast magnetic resonance imaging (PC-MRI) measurement is investigated using a computational fluid dynamics (CFD) model with the objective to determine the magnitude of the flow underestimation due to turbulence behind a narrowed valve in a phantom experiment. An acrylic stationary flow phantom is used with three insertable plates mimicking aortic valvular stenoses of varying degrees. Positive and negative horizontal fluxes are measured at equidistant slices using standard PC-MRI sequences by 1.5T and 3T systems. The CFD model is based on the 3D lattice Boltzmann method (LBM). The experimental and simulated data are compared using the Bland-Altman-derived limits of agreement. Based on the LBM results, the turbulence is quantified and confronted with the level of flow underestimation. LBM gives comparable results to PC-MRI for valves up to moderate stenosis on both field strengths. The flow magnitude through a severely stenotic valve was underestimated due to signal void in the regions of turbulent flow behind the valve, consistently with the level of quantified turbulence intensity. Flow measured by PC-MRI is affected by noise and turbulence. LBM can simulate turbulent flow efficiently and accurately, it has therefore the potential to improve clinical interpretation of PC-MRI.

Abstract TP483: Transcatheter Aortic Valve Replacement (TAVR) Does Not Improve Cerebral Hemodynamics or Neurocognition in Patients With Severe Aortic Stenosis

Objective: To determine if aortic stenosis (AS) is associated with altered cerebral hemodynamics and impaired neurocognition, and whether TAVR improves hemodynamics and cognition. Background: AS results in higher systolic pressure to overcome resistance from the stenotic valve, leading to heart failure and decline in cardiac output. There has been no baseline assessment of CBF with neurocognition in AS, or the effects of valve replacement. Methods: In 40 patients with planned TAVR, transcranial Doppler (TCD) assessed bilateral MCA mean flow velocity (MFV); abnormality was < 30cc/sec. The neurocognitive battery assessed memory, language, attention, visual-spatial skills, and executive function, yielding an average Z-score. Impairment was < 1.5 SD’s below the normative mean. Results: The mean age was 78 years, 59% male, and the mean valve gradient was 46.87%. Mean follow-up was 36 days post-TAVR (range 27 - 55). Before TAVR, the average MFV was 42 cc/sec (SD=10.22), and the mean cognitive score was -0.22 SD’s (range -1.99 to 1.08) below the normative mean. Of the 5 with abnormal MFV’s, none had abnormal cognition (average=0.19 SD’s above the normative mean). After TAVR, the MFV was 43 cc/sec, not different from baseline (p=0.56). The post-TAVR average Z-score was 0.01 SD’s above the normative mean, also not different from baseline (p=0.29). There was no correlation between the change scores in MFV and in neurocognition (r = 0.08, p= 0.69). Conclusions: Among patients with severe AS, there was no correlation at baseline between abnormal MFV’s on TCD and abnormal neurocognition. It was therefore unsurprising that there was little impact of valve replacement on these measures of cerebral blood flow and brain function. Prior assumptions about diminished CBF and the relationship to cognitive function may not be supported.

A biomechanical model of the pathological aortic valve: simulation of aortic stenosis

Aortic stenosis (AS) disease is a narrowing of the aortic valve (AV) opening which reduces blood flow from the heart causing several health complications. Although a lot of work has been done in AV simulations, most of the efforts have been conducted regarding healthy valves. In this article, a new three-dimensional patient-specific biomechanical model of the valve, based on a parametric formulation of the stenosis that permits the simulation of different degrees of pathology, is presented. The formulation is based on a double approach: the first one is done from the geometric point of view, reducing the effective ejection area of the AV by joining leaflets using a zipper effect to sew them; the second one, in terms of functionality, is based on the modification of AV tissue properties due to the effect of calcifications. Both healthy and stenotic valves were created using patient-specific data and results of the numerical simulation of the valve function are provided. Analysis of the results shows a variation in the first principal stress, geometric orifice area, and blood velocity which were validated against clinical data. Thus, the possibility to create a pipeline which allows the integration of patient-specific data from echocardiographic images and iFR studies to perform finite elements analysis is proved.

1641 Bicuspid pulmonary valve - an unusual cause of dilated pulmonary artery

Abstract Introduction Dilated pulmonary artery is a common finding with a variety of possible aetiologies. We present a case of unexplained dilated pulmonary artery that was associated with bicuspid pulmonary valve identified by CMR. Case Presentation A 67-year-old female underwent mitral valve repair for severe mitral regurgitation. She had presented with breathlessness, and had severe mitral regurgitation due to a myxomatous valve with bileaflet prolapse, confirmed with TOE. Echo showed: normal LV dimensions, LVEF 66%. RV size and systolic function normal. Coronary angiography was normal and pulmonary hypertension was not present on right heart catheterization. At postoperative follow up she was well and asymptomatic, with echo showing good LV systolic function, intact mitral valve repair, and normal systolic pulmonary artery pressures (36mmHg). New T wave inversion was identified across the precordial leads so a CMR was performed. CMR showed normal LV volumes and function with no wall motion abnormality or LVH. There was no fibrosis or infarction in the late phase after Gadolinium contrast. The RV was dilated (73mm diameter at base) with normal systolic function. The main pulmonary artery was dilated at 42mm. Flow mapping showed no evidence of shunt (Qp:Qs = 1:1) and the atrial septum was intact. Pulmonary valve function was normal but the valve was bicuspid in morphology. Discussion Bicuspid pulmonary valve is a rare finding. In our case this was identified by CMR and was associated with a dilated pulmonary artery. Bicuspid pulmonary valve is most commonly identified in the context of pulmonary valve stenosis. Isolated pulmonary valve stenosis is a rare finding; it is most often associated with other congenital defects like Fallot. Pulmonary stenosis has been associated with pulmonary artery aneurysm, attributed to hemodynamic changes caused by the stenotic valve. However as with bicuspid aortic valve it is recognized that the "post stenotic dilation" is part of the pathology of bicuspid valve and does not need the changed haemodynamics of a stenotic valve. During embryogenesis neural crest cells are necessary for the normal development of the semilunar valves, the septation of the outflow tract into the aorta and pulmonary artery, and the remodeling of the aortic arch. Any defect in this migration can cause abnormalities or aneurysm of the aorta or pulmonary artery together with semilunar valve defects. A study of 3,861 donor hearts dissected at the European Homograft Bank revealed only four cases (0.1%) of bicuspid pulmonary valves. Bicuspid pulmonary valve with normal function can be difficult to identify at echocardiography. It can be well visualized by CMR and this can be combined with an assessment of the pulmonary arteries. It should be remembered as a rarer cause of dilated pulmonary artery when other causes have been excluded. Figure A. Dilated MPA. B. Dilated RV. C. and D. Bicuspid pulmonary valve. Abstract 1641 Figure. Dilated MPA. Bicuspid pulmonary valve

P167 The burden of post-actinic heart disease: a case of severe valvular and coronary artery disease in a cancer survivor

Abstract Background A 47-year old female complaining of exertional dyspnoea (NYHA class III) was admitted at our Cardiology department. She had a history of nodular sclerosis Hodgkin lymphoma (HL), treated with chemo- and radiotherapy, and complicated by post-actinic pneumopathy and cardiopathy. At the age of 39, she had undergone coronary artery bypass grafting with left internal mammal artery (LIMA) to left anterior descendent artery and saphenous vein to obtuse marginal branch, and aortic valve replacement with a mechanical prosthesis due to severe aortic stenosis. Some years later, she had undergone percutaneous stenting of the left main (LM) due to occlusion of the LIMA bypass graft. At admission, the patient was hemodynamically stable, with signs of right-sided congestive heart failure. Both 2D and 3D transthoracic echocardiogram (TTE) showed preserved biventricular function, normal function of the aortic prosthesis, and diffuse calcification of the whole mitral valve apparatus, involving the leaflets, the annulus, the tendinous chords and the anterolateral papillary muscle (Figure Panels A-B), causing severe mitral stenosis (mean gradient 10 mmHg, 3D planimetric area 0.9 cm2, Wilkins score 12) and moderate organic insufficiency (Panel C). The tricuspid valve was also affected, with thickened, hypomobile leaflets, causing mild stenosis (mean gradient 4 mmHg, 3D planimetric area 3.8 cm2) and severe insufficiency (Panel D). Transesophageal echocardiogram (TOE) couldn"t be performed because of actinic oesophagitis. Percutaneous valvuloplasty was contraindicated due to moderate mitral insufficiency, high Wilkins score and a huge amount of calcium affecting the whole valve apparatus but sparing the commissures. The patient was scheduled to PCI on the LM due to intrastent restenosis, but died during the procedure as a consequence of an intrastent massive thrombosis leading to cardiac arrest. Learning points Hodgkin lymphoma survivors are at increased cardiovascular and intraoperative risk. Old radiotherapy protocols for HL may cause severe post-actinic valvular and coronary disease. Post-actinic valvular heart disease often affects aortic and mitral valve more than a decade after irradiation, and may manifest as stenosis, insufficiency or both. Organic regurgitation and stenosis of tricuspid valve are uncommon, but may also occur and lead to worse patient outcome. Despite TOE may bring additional valuable informations in challenging cases, the coexistence of oesophageal sequelae from post-actinic oesophagitis may limit its applicability. TTE is the first line and often the only diagnostic tool available for identifying the characteristic valvular lesions in cancer survivors exposed to radiotherapy. 3D TTE may be particularly useful to identify subtle signs of primary involvement of tricuspid apparatus and quantify the anatomical area of a stenotic tricuspid valve, when severe regurgitation coexists and transvalvular gradients may be unreliable. Abstract P167 Figure

P641 Severe pulmonary steno-insufficiency due to metastatic carcinoid tumor in a 57 years old patient treated with MTPV implantation: first experience

Abstract Funding Acknowledgements none Background Right side heart valve involvement is a well known phenomenon in metastatic carcinoid disease. In recent times bioprosthetic valves have been widely used for replacement of stenotic and regurgitant native heart valves. Melody Transcatheter Pulmonary Valve (MTPV, Medtronic, Minneapolis, MN, USA) has been approved for treatment of native pulmonary valves as well as failing biological prostheses and conduits. We present the first case to our knowledge of severe native pulmonary valve steno-insufficiency due to metastatic carcinoid syndrome treated with MTPV implantation. Case report A 57-year-old woman is known since 2007 for metastatic carcinoid syndrome treated with surgical resection followed by chemotherapy (tamoxifene, everolimus) and radiotherapy. For 2 years she has been known for tricuspid and pulmonary involvement, which aggravated progressively, leading to symptomatic right heart failure. She was therefore submitted for multimodality imaging evaluation (see picture) and right heart catheterization. Transthoracic echocardiogram, cardiac MRI and right heart catheterization confirmed severe pulmonary valve steno-insufficiency. Cardiopulmonary exercise testing revealed a severe limitation of aerobic exercise capacity (VO2 max 14.4 ml/min/kg). After heart team discussion it was decided to treat the patient in a 2 step approach, initially with implantation of a Melody valve in pulmonary position and subsequently with surgical repair of the tricuspid valve. Pulmonary valve was treated by placement of a 39 x 25 mm ANDRA stent and subsequent implantation of a 22 mm Melody valve. Before stenting, coronary angiography with simultaneous balloon inflation in RVOT was performed to exclude coronary artery compression. During the procedure the patient developed hypotension, which was treated effectively with Octeotride. Post-operative echocardiogram showed a significant reduction in pulmonary valve gradient and no significant residual regurgitation. Conclusions We treated effectively severe pulmonary steno-insufficiency due to metastatic carcinoid tumor with MTPV implantation. No complications occurred. Multimodality imaging is fundamental for patients selection and preoperative planning of prosthetic valve dimensions. Abstract P641 Figure. Multimodality imaging of PV

Valve Interstitial Cell-Specific Cyclooxygenase-1 Associated With Calcification of Aortic Valves

The molecular mechanisms underlying aortic valve calcification are poorly understood. Here, we aimed to identify the master regulators of calcification by comparison of genes in valve interstitial cells (VICs) with calcified and noncalcified aortic valves. Calcified aortic valves were surgically excised from patients with aortic valve stenosis who required aortic valve replacements. Noncalcified and calcified sections were obtained from aortic valve leaflets. Collagenase-digested tissues were seeded into dishes, and VICs adhering to the dishes were cultured for 3 weeks, followed by comprehensive gene expression analysis. Functional analyses of identified proteins were performed by invitro calcification assays. Tissue localization was determined by immunohistochemical staining for normal (n= 11) and stenotic valves (n= 30). We found 87 genes showing greater than a twofold change in calcified tissues. Among these genes, 68were downregulated and 19 were upregulated. Cyclooxygenase-1 (COX1) messenger RNA and protein levels were upregulated in VICs from calcified tissues. The COX1 messenger RNA and protein levels in VICs were also strongly increased by stimulation with osteoblast differentiation medium. These were VIC-specific phenotypes and were not observed in other cell types. Immunohistochemical staining revealed that COX1-positive VICs were specifically localized in the calcified area of aortic valve tissues. The VIC-specific COX1 overexpression played a crucial role in calcification by promoting osteoblast differentiation in aortic valve tissues.

P6504NETosis is associated with the severity of aortic stenosis

Abstract Background High hemodynamic forces similar to those observed in aortic stenosis (AS) can trigger neutrophil extracellular traps (NETs) formation. Purpose An involvement of NETosis in the AS pathogenesis is unknown. Methods We enrolled 25 patients, median age 64.9 [range, 58–69] years with isolated severe AS (transvalvular pressure gradient, PGmean: 53.6±11.3 mm Hg, PGmax: 85.1±17.6 mmHg), after aortic valve replacement and 15 healthy sex/age-matched controls. Autopsy-derived aortic valves from 5 healthy donors served as negative control. Transverse valve sections were taken from the mid and commissural areas of the leaflet and cryosectioned by a Leica CM 1520 cryostat. Valvular expression of citrullinated histone H3 (citH3), together with myeloperoxidase (MPO), and neutrophil elastase (NE) as NETs biomarkers and macrophages (CD68) were evaluated by single- and double- immunostaining. Plasma concentrations of citH3 and interleukin 6 (IL-6) were also determined. Results All stenotic and healthy valves expressed citH3 in the leaflets' endothelial and sub-endothelial layers at the aortic side. The in loco expression of citH3-positive cells was higher in AS patients compared with controls (42.3±8.7% vs. 7.2±4.8%, p<0.05) and correlated with disease severity measured as aortic valve area (AVA; r=−0.84, p<0.0001), as well as PGmean (r=0.62, p<0.001), and PGmax (r=0.52, p>0.05). Double-staining revealed that within stenotic leaflets 28.3±8.4% of cells were citH3/MPO- and 25.2±7.1% citH3/NE-positive. None of control valves showed MPO or NE-positivity. Moreover, 6.6±1.9% of valvular cells (17.2±5.4% of citH3-positive cells) showed citH3/CD68 double-positivity and were identified as macrophages. Plasma levels of citH3 were 59% higher in AS patients then in controls (p<0.05), and the concentrations of citH3 correlated with IL-6 levels (r=0.44, p<0.05) and AVA (r=−0.48, p<0.05). Conclusions The presence of NETs in stenotic valves and association with AS severity might suggest novel mechanisms involved in the disease progression. This work was supported by the grant from the Polish National Science Center (DEC-2017/01/X/NZ5/02006 to R.K-T.). Acknowledgement/Funding This work was supported by the grant from the Polish National Science Center (DEC-2017/01/X/NZ5/02006 to R.K-T.).

P5988Non-classical Ly6C-low monocytes contribute to aortic valve stenosis development in mice

Abstract Introduction Aortic valve stenosis (AS) is one of the most common valvular diseases in the western world. Once patients with AS develop symptoms mortality increases up to 50% over two years. For many years AS was believed to be a passive degenerative process. Recent findings suggest a more complex pathomechanism with a strict molecular and cellular regulation involving local inflammation and invasion of immune cells. Specifically, pro-inflammatory macrophages have been shown to play an important role in disease progression. On the other hand, monocyte counts in the peripheral blood of patients with severe AS are significantly decreased and there is an inverse correlation between valve orifice area and circulating monocyte count. In order to elucidate the exact function of pro-inflammatory classical (Ly6C-high) and non-classical (Ly6C-low) monocytes in disease initiation processes, we conducted a series of experiments in a model of murine AS. Methods In this study 10–12 weeks old male C57BL6/J or CX3CR1-deficient mice were investigated. For AS induction, a coronary springwire was introduced into the left ventricle, pushed and rotated over the aortic valve under echocardiographic guidance. In sham operated mice the wire was only inserted into the left carotid artery without manipulation of the aortic valve. Development of AS was confirmed via weekly ultrasound examinations. Immune cells in the aortic valve were quantified using flow cytometry and immunofluorescence microscopy. Results Ultrasound analysis after two weeks confirmed the development of AS in the injured wildtype mice. Transaortic peak velocity levels were significantly increased compared to sham operated mice. Flow cytometry of explanted aortic valves showed a strong cellular immunoreaction in the stenotic valves. The amount of anti-inflammatory Ly6C-low monocytes was significantly increased compared to sham-mice, whereas the number of pro-inflammatory Ly6C-high monocytes remained stable. Interestingly CD-4 positive T-cells were augmented in stenotic aortic valves. Immunofluorescence confirmed Ly6C-low monocytes infiltration in the valve, in close proximity to the endothelial cells on the ventricular and the aortic side. The expression of recruitment and adhesion markers CD11b and CX3CR1 were significantly increased on the surface of the Ly6C-low monocytes of AS mice. To investigate the role of Ly6C-low monocytes in AS development, CX3CR1 deficient mice, which are not able to recruit non-classical monocytes via CX3CR1, were subjected to aortic valve wire injury. After two weeks, peak velocity levels in CX3CR1−/− mice remained nearly unchanged and were significantly decreased compared to wildtype mice. Conclusion Our data suggest that non-classical Ly6Clow monocytes play a crucial role in AS development in mice. Therefore, they may be targets for future therapeutic interventions. Acknowledgement/Funding S.T.N. was funded by Else-Kröner-Fresenius-Foundation of the Medical Faculty of the University of Bonn

2571 Unicentric Castleman Disease as a Cause of Ileal Perforation: A Case Report

INTRODUCTION: Castleman disease is describes a group of heterogenous lymphoproliferative disorders that share histopathologic features. It is divided into Unicentric castleman disease (UCD) and Multicentric Castleman disease. We present a case of a patient with one year history of recurrent small bowel obstruction (SBO), which was found to be due to UCD affecting the mesentery. CASE DESCRIPTION/METHODS: A 75 years old gentleman initially presented one year ago with an episode of SBO. He had no history of abdominal or pelvic surgery. CT scan showed a transition point near the terminal ileum and mesenteric/retroperitoneal lymphadenopathy. Patient underwent a colonoscopy which showed a stenotic ileocecal valve with active colitis in the terminal ileum and ascending colon suggestive of resolving intestinal ischemia. This time, patient was admitted with decreased oral intake due to SBO. He was found to have a low albumin of 0.8 and an AKI on CKD. He also had bilateral pleural effusions and new ascites. He was treated conservatively initially, but he developed new abdominal pain with X ray showing free air under the diaphragm concerning for intestinal perforation. Patient underwent emergent laparotomy, where he had a perforated terminal ileum and multiple large fibrotic lymph nodes in the associated mesentery. Pathology showed proliferation of atretic follicles. There were occasional penetrating capillaries and the mantle lymphocytes have an onion-skin pattern. The interfollicular zones showed increased plasma cells, but not prominent vascular proliferation. CD3 and CD20 stains showed an intact immune-architecture. The overall findings showed a mixed pattern of Castleman lymphadenopathy, with some features of both the hyaline vascular and plasma cell variants. He had IgA of 510 mg/dl and an abnormal SPEP with IgG lambda paraprotein of 0.39 g/dl. His hospital course was complicated by septic shock due to bacterial and fungal peritonitis. Patient eventually went into cardiac arrest and died. DISCUSSION: Mixed variant CD is mostly multicentric, however, some patients with UCD reveal features of both hyaline vascular type and plasma cell type. In this case, apart from abdominal pain and recurrent SBO episodes, there were no other complaints. Acute phase reactants, CBC, and serological testing for HIV, HHV-8, Hepatitis B, Hepatitis C, RPR and PPD were all unremarkable. UCD is usually asymptomatic and generally curable using surgical resection but in this case led to severe complication ending in patient's demise.

Flow disturbances and the development of endocardial fibroelastosis

ObjectivesEndothelial-to-mesenchymal transition (EndMT) has been identified as the underlying mechanism of endocardial fibroelastosis (EFE) formation. The purpose of this study was to determine whether hemodynamic alterations due to valvar defects promote EndMT and whether age-specific structural changes affect ventricular diastolic compliance despite extensive surgical resection of EFE tissue. Material and MethodsWe analyzed EFE tissue from 24 patients with hypoplastic left heart syndrome (HLHS) who underwent left ventricular (LV) rehabilitation surgery at Boston Children's Hospital between December 2011 and March 2018. Six patients with flow disturbances across the aortic valve and/or mitral valve but no HLHS diagnosis and macroscopic appearance of “EFE-like tissue” in the LV were included for comparison. All samples were examined for amount of collagen/elastin production and degradation, and presence of active EndMT by histologic analysis. ResultsEFE tissue from patients with and without HLHS consisted predominantly of elastin and collagen fibers. There was no alteration in degradation activity for collagen or elastin as shown by in situ zymography. Active EndMT was found in all patients with and without HLHS with flow disturbances (“EFE-like”). In patients with HLHS, EFE infiltrated into the underlying myocardium with increasing age. ConclusionsPatients with and without HLHS with flow disturbances due to stenotic or incompetent valves develop EndMT-derived fibrotic tissue covering the LV. When EFE recurs, it is directly associated with flow disturbances and switches to an infiltrative growth pattern with increasing age, leading to increased diastolic stiffness of the LV.

Biomechanical modeling of transcatheter aortic valve replacement in a stenotic bicuspid aortic valve: deployments and paravalvular leakage.

Calcific aortic valve disease (CAVD) is characterized by stiffened aortic valve leaflets. Bicuspid aortic valve (BAV) is the most common congenital heart disease. Transcatheter aortic valve replacement (TAVR) is a treatment approach for CAVD where a stent with mounted bioprosthetic valve is deployed on the stenotic valve. Performing TAVR in calcified BAV patients may be associated with post-procedural complications due to the BAV asymmetrical structure. This study aims to develop refined computational models simulating the deployments of Evolut R and PRO TAVR devices in a representative calcified BAV. The paravalvular leakage (PVL) was also calculated by computational fluid dynamics simulations. Computed tomography scan of severely stenotic BAV patient was acquired. The 3D calcium deposits were generated and embedded inside a parametric model of the BAV. Deployments of the Evolut R and PRO inside the calcified BAV were simulated in five bioprosthesis leaflet orientations. The hypothesis of asymmetric and elliptic stent deployment was confirmed. Positioning the bioprosthesis commissures aligned with the native commissures yielded the lowest PVL (15.7 vs. 29.5mL/beat). The Evolut PRO reduced the PVL in half compared with the Evolut R (15.7 vs. 28.7mL/beat). The proposed biomechanical computational model could optimize future TAVR treatment in BAV patients. Graphical abstract.

Fluid dynamics of thoracic cavity venous flow in multiple sclerosis

This paper hypothesizes, based on fluid dynamics principles, that in multiple sclerosis (MS) non-laminar, vortex blood flow occurs in the superior vena cava (SVC) and brachiocephalic veins (BVs), particularly at junctions with their tributary veins. The physics-based analysis demonstrates that the morphology and physical attributes of the major thoracic veins, and their tributary confluent veins, together with the attributes of the flowing blood, predict transition from laminar to non-laminar flow, primarily vortex flow, at select vein curvatures and junctions.Non-laminar, vortex flow results in the development of immobile stenotic valves and intraluminal flow obstructions, particularly in the internal jugular veins (IJVs) and in the azygos vein (AV) at their confluences with the SVC or BVs.Clinical trials’ observations of vascular flow show that regions of low and reversing flow are associated with endothelial malformation. The physics-based analysis predicts the growth of intraluminal flaps and septa at segments of vein curvature and flow confluences. The analysis demonstrates positive correlations between predicted and clinically observed elongation of valve leaflets and between the predicted and observed prevalence of immobile valves at various venous flow confluences. The analysis predicts the formation of sclerotic plaques at venous junctions and curvatures, in locations that are analogous to plaques in atherosclerosis.The analysis predicts that increasing venous compliance increases the laminarity of venous flow and reduces the prevalence and severity of vein malformations and plaques, a potentially significant clinical result.An over-arching observation is that the correlations between predicted phenomena and clinically observed phenomena are sufficiently positive that the physics-based approach represents a new means for understanding the relationships between venous flow in MS and clinically observed venous malformations.

Fluid dynamics of cerebrospinal venous flow in multiple sclerosis

Stenotic immobile valves and other malformations obstruct normal cerebrospinal venous outflow, resulting in reflux flow which combines with the normal outflow to produce standing pressure waves in the internal jugular and other cerebrospinal veins. It is hypothesized that, if the cerebrospinal venous structure between the obstruction and the deep cerebral veins is sufficiently non-compliant, the standing wave will result in bidirectional flow in the fine cerebral veins. Bidirectional flow in the fine veins, over extended periods of time, will cause disorder in the veins’ endothelial morphology, and ultimately, result in the disruption of the blood-brain barrier as observed in multiple sclerosis.This physics-based analysis demonstrates a positive correlation between clinically observed MS attributes with the predicted flow patterns and venous malformations that are based on fluid dynamics principles that include venous compliance influences.The physics-based approach used in this analysis provides new insights into MS pathologies based on predicted pressure and flow patterns.

Nucleotide ecto-enzyme metabolic pattern and spatial distribution in calcific aortic valve disease; its relation to pathological changes and clinical presentation

BackgroundExtracellular nucleotide metabolism contributes to chronic inflammation, cell differentiation, and tissue mineralization by controlling nucleotide and adenosine concentrations and hence its purinergic effects. This study investigated location-specific changes of extracellular nucleotide metabolism in aortic valves of patients with calcific aortic valve disease (CAVD). Individual ecto-enzymes and adenosine receptors involved were analyzed together with correlation with CAVD severity and risk factors.ResultsNucleotide and adenosine degradation rates were adversely modified on the aortic surface of stenotic valve as compared to ventricular side, including decreased ATP removal (1.25 ± 0.35 vs. 2.24 ± 0.61 nmol/min/cm2) and adenosine production (1.32 ± 0.12 vs. 2.49 ± 0.28 nmol/min/cm2) as well as increased adenosine deamination (1.28 ± 0.31 vs. 0.67 ± 0.11 nmol/min/cm2). The rates of nucleotide to adenosine conversions were lower, while adenosine deamination was higher on the aortic sides of stenotic vs. non-stenotic valve. There were no differences in extracellular nucleotide metabolism between aortic and ventricular sides of non-stenotic valves. Furthermore, nucleotide degradation rates, measured on aortic side in CAVD (n = 62), negatively correlated with echocardiographic and biochemical parameters of disease severity (aortic jet velocity vs. ATP hydrolysis: r = − 0.30, p < 0.05; vs. AMP hydrolysis: r = − 0.44, p < 0.001; valvular phosphate concentration vs. ATP hydrolysis: r = − 0.26, p < 0.05; vs. AMP hydrolysis: r = − 0.25, p = 0.05) while adenosine deamination showed positive correlation trend with valvular phosphate deposits (r = 0.23, p = 0.07). Nucleotide and adenosine conversion rates also correlated with CAVD risk factors, including hyperlipidemia (AMP hydrolysis vs. serum LDL cholesterol: r = − 0.28, p = 0.05; adenosine deamination vs. total cholesterol: r = 0.25, p = 0.05; LDL cholesterol: r = 0.28, p < 0.05; triglycerides: r = 0.32, p < 0.05), hypertension (adenosine deamination vs. systolic blood pressure: r = 0.28, p < 0.05) and thrombosis (ATP hydrolysis vs. prothrombin time: r = − 0.35, p < 0.01). Functional assays as well as histological and immunofluorescence, flow cytometry and RT-PCR studies identified all major ecto-enzymes engaged in nucleotide metabolism in aortic valves that included ecto-nucleotidases, alkaline phosphatase, and ecto-adenosine deaminase. We have shown that changes in nucleotide-converting ecto-enzymes were derived from their altered activities on valve cells and immune cell infiltrate. We have also demonstrated a presence of A1, A2a and A2b adenosine receptors with diminished expression of A2a and A2b in stenotic vs. non-stenotic valves. Finally, we revealed that augmenting adenosine effects by blocking adenosine deamination with deoxycoformycin decreased aortic valve thickness and reduced markers of calcification via adenosine-dependent pathways in a mouse model of CAVD.ConclusionsThis work highlights profound changes in extracellular nucleotide and adenosine metabolism in CAVD. Altered extracellular nucleotide hydrolysis and degradation of adenosine in stenotic valves may affect purinergic responses to support a pro-stenotic milieu and valve calcification. This emphasizes a potential mechanism and target for prevention and therapy.Graphic abstract.

Modeling of the Instantaneous Transvalvular Pressure Gradient in Aortic Stenosis.

The simplified and modified Bernoulli equations break down in estimating the true pressure gradient across the stenotic aortic valve due to their over simplifying assumptions of steady and inviscid conditions as well as the fundamental nature in which aortic valves are different than idealized orifices. Nevertheless, despite having newer models based on time-dependent momentum balance across an orifice, the simplified and modified Bernoulli continue to be the clinical standard because to date, they remain the only models clinically implementable. The objective of this study is to (1) illustrate the fundamental considerations necessary to accurately model the time-dependent instantaneous pressure gradient across a fixed orifice and (2) propose empirical corrections when applying orifice based models to severely stenotic aortic valves. We introduce a general model to predict the time-dependent instantaneous pressure gradient across an orifice that explicitly model the Reynolds number dependence of both the steady and unsteady terms. The accuracy of this general model is assessed with respect to previous models through pulse duplicator experiments on a round orifice model as well as an explanted stenotic surgical aortic valve both with geometric areas of 0.6cm2 (less than 1cm2 which is the threshold for stenosis determination) over cardiac outputs of 3 and 5L/min and heart rates of 60, 90 and 120bpm. The model and the raw experimental data corresponding to the orifice showed good agreement over a wide range of cardiac outputs and heart rates (R2 exceeding 0.91). The derived average and peak transvalvular pressure gradients also demonstrated good agreement with no significant differences between the respective peaks (p > 0.09). The new model proposed holds promise with its physical and closed form representation of pressure drop, however accurate modeling of the time-variability of the valve area is necessary for the model to be applied on stenotic valves.

NETosis is associated with the severity of aortic stenosis: Links with inflammation

BackgroundAn involvement of neutrophil extracellular traps (NETs) in the aortic stenosis (AS) pathogenesis is unknown. MethodsWe enrolled 50 patients, median age 66.5 years with isolated severe AS, after aortic valve replacement and 20 healthy sex/age-matched controls. Autopsy-derived aortic valves from 5 healthy donors served as controls. Valvular expression of citrullinated histone H3 (citH3), myeloperoxidase (MPO), and neutrophil elastase (NE) and macrophages (CD68) were evaluated by immunostaining. Plasma citH3 and interleukin 6 (IL-6) were also determined. ResultsAll stenotic and healthy valves expressed citH3 in the leaflets' endothelial and sub-endothelial layers at the aortic side. Amount of valvular citH3-positive cells was higher in AS patients compared with controls (53.5 [33–62]% vs. 5.7 [4.1–9.0]%, p < 0.0001) and correlated with aortic valve area (AVA; r = −0.69, p < 0.0001) and mean transvalvular gradient (r = 0.6, p < 0.0001). Double-staining revealed that in AS valves 27.2 ± 9.8% of cells were citH3/MPO- and 25.3 ± 8.9% citH3/NE-positive. Within stenotic valves, 6.4 ± 2.5% of cells showed citH3/CD68 double-positivity and were identified as macrophages. AS patients compared to controls had 83% higher plasma citH3 (p < 0.0001). In AS, plasma citH3 correlated with IL-6 (r = 0.39, p = 0.0054) levels and AVA (r = −0.45, p = 0.0009). ConclusionsThe presence of NETs in stenotic valves and association with AS severity suggest novel mechanisms involved in the disease progression.

Identification of miR-143 as a Major Contributor for Human Stenotic Aortic Valve Disease.

Calcification of aortic valves leads to aortic stenosis mainly in elderly individuals, but the underlying molecular mechanisms are still not understood. Here, we studied microRNA (miR, miRNA) expression and function in healthy and stenotic human aortic valves. We identified miR-21, miR-24, and miR-143 to be highly upregulated in stenotic aortic valves. Using luciferase reporter systems, we found direct binding of miR-143 to the 3'UTR region of the matrix gla protein (MGP), which in turn is a key factor to sustain homeostasis in aortic valves. In subsequent experiments, we demonstrated a therapeutic potential of miRNA regulation during calcification in cardiac valvular interstitial cells. Collectively, our data provide evidence that deregulated miR expression contributes to the development of stenotic valve disease and thus form novel therapeutic opportunities of this severe cardiovascular disease.