Fragmentation of Different Calcification Growth Patterns in Bicuspid Valves During Balloon Valvuloplasty Procedure.

This study focuses on the calcification development and routes of type-1 bicuspid aortic valves based on CT scans and the effect of the unique geometrical shapes of calcium deposits on their fragmentation under balloon valvuloplasty procedures. Towards this goal, the novel Reverse Calcification Technique (RCT), which can predict the calcification progression leading to the current state based on CT scans, is utilized for n = 26 bicuspid aortic valves patients. Two main calcification patterns of type-1 bicuspid aortic valves were identified; asymmetric and symmetric with either partial or full arcs and circles. Subsequently, a calcification fragmentation biomechanical model was introduced to study the balloon valvuloplasty procedure prior to transcatheter aortic valve replacement implantation that allows better device expansion. To achieve this goal, six representative stenotic bicuspid aortic valves of different calcification patterns were investigated. It was found that the distinct geometrical shape of the calcium deposits had a significant effect on the cracks' initiations. Full or partial circle deposits had stronger resistance to fragmentation and mainly remained intact, yet, arc-shaped pattern deposits resulted in multiple cracks in bottleneck regions. The proposed biomechanical computational models could help assess calcification fragmentation patterns toward improving treatment approaches in stenotic bicuspid aortic valve patients, particularly for the off-label use of transcatheter aortic valve replacement.

Progressive Calcification in Bicuspid Valves: A Coupled Hemodynamics and Multiscale Structural Computations.

Bicuspid aortic valve (BAV) is the most common congenital heart disease. Calcific aortic valve disease (CAVD) accounts for the majority of aortic stenosis (AS) cases. Half of the patients diagnosed with AS have a BAV, which has an accelerated progression rate. This study aims to develop a computational modeling approach of both the calcification progression in BAV, and its biomechanical response incorporating fluid-structure interaction (FSI) simulations during the disease progression. The calcification is patient-specifically reconstructed from Micro-CT images of excised calcified BAV leaflets, and processed with a novel reverse calcification technique that predicts prior states of CAVD using a density-based criterion, resulting in a multilayered calcified structure. Four progressive multilayered calcified BAV models were generated: healthy, mild, moderate, and severe, and were modeled by FSI simulations during the full cardiac cycle. A valve apparatus model, composed of the excised calcified BAV leaflets, was tested in an in-vitro pulse duplicator, to validate the severe model. The healthy model was validated against echocardiography scans. Progressive AS was characterized by higher systolic jet flow velocities (2.08, 2.3, 3.37, and 3.85 m s-1), which induced intense vortices surrounding the jet, coupled with irregular recirculation backflow patterns that elevated viscous shear stresses on the leaflets. This study shed light on the fluid-structure mechanism that drives CAVD progression in BAV patients.

Platelet Dysfunction During Mechanical Circulatory Support: Elevated Shear Stress Promotes Downregulation of αIIbß3 and GPIb via Microparticle Shedding Decreasing Platelet Aggregability.

[Figure: see text].

Platelet Activation via Shear Stress Exposure Induces a Differing Pattern of Biomarkers of Activation versus Biochemical Agonists.

BACKGROUND: Implantable cardiovascular therapeutic devices, while hemodynamically effective, remain limited by thrombosis. A driver of device-associated thrombosis is shear-mediated platelet activation (SMPA). Underlying mechanisms of SMPA, as well as useful biomarkers able to detect and discriminate mechanical versus biochemical platelet activation, are poorly defined. We hypothesized that SMPA induces a differing pattern of biomarkers compared with biochemical agonists. METHODS: Gel-filtered human platelets were subjected to mechanical activation via either uniform constant or dynamic shear; or to biochemical activation by adenosine diphosphate (ADP), thrombin receptor-activating peptide 6 (TRAP-6), thrombin, collagen, epinephrine, or arachidonic acid. Markers of platelet activation (P-selectin, integrin αIIbß3 activation) and apoptosis (mitochondrial membrane potential, caspase 3 activation, and phosphatidylserine externalization [PSE]) were examined using flow cytometry. Platelet procoagulant activity was detected by chromogenic assay measuring thrombin generation. Contribution of platelet calcium flux in SMPA was tested employing calcium chelators, ethylenediaminetetraacetic acid (EDTA), and BAPTA-AM. RESULTS: Platelet exposure to continuous shear stress, but not biochemical agonists, resulted in a dramatic increase of PSE and procoagulant activity, while no integrin αIIbß3 activation occurred, and P-selectin levels remained barely elevated. SMPA was associated with dissipation of mitochondrial membrane potential, but no caspase 3 activation was observed. Shear-mediated PSE was significantly decreased by chelation of extracellular calcium with EDTA, while intracellular calcium depletion with BAPTA-AM had no significant effect. In contrast, biochemical agonists ADP, TRAP-6, arachidonic acid, and thrombin were potent inducers of αIIbß3 activation and/or P-selectin exposure. This differing pattern of biomarkers seen for SMPA for continuous uniform shear was replicated in platelets exposed to dynamic shear stress via circulation through a ventricular assist device-propelled circulatory loop. CONCLUSION: Elevated shear stress, but not biochemical agonists, induces a differing pattern of platelet biomarkers-with enhanced PSE and thrombin generation on the platelet surface. This differential biomarker phenotype of SMPA offers the potential for early detection and discrimination from that mediated by biochemical agonists.

In Vitro Durability and Stability Testing of a Novel Polymeric Transcatheter Aortic Valve.

Transcatheter aortic valve replacement (TAVR) has emerged as an effective therapy for the unmet clinical need of inoperable patients with severe aortic stenosis (AS). Current clinically used tissue TAVR valves suffer from limited durability that hampers TAVR's rapid expansion to younger, lower risk patients. Polymeric TAVR valves optimized for hemodynamic performance, hemocompatibility, extended durability, and resistance to calcific degeneration offer a viable solution to this challenge. We present extensive in vitro durability and stability testing of a novel polymeric TAVR valve (PolyNova valve) using 1) accelerated wear testing (AWT, ISO 5840); 2) calcification susceptibility (in the AWT)-compared with clinically used tissue valves; and 3) extended crimping stability (valves crimped to 16 Fr for 8 days). Hydrodynamic testing was performed every 50M cycles. The valves were also evaluated visually for structural integrity and by scanning electron microscopy for evaluation of surface damage in the micro-scale. Calcium and phosphorus deposition was evaluated using micro-computed tomography (µCT) and inductive coupled plasma spectroscopy. The valves passed 400M cycles in the AWT without failure. The effective orifice area kept stable at 1.8 cm with a desired gradual decrease in transvalvular pressure gradient and regurgitation (10.4 mm Hg and 6.9%, respectively). Calcium and phosphorus deposition was significantly lower in the polymeric valve: down by a factor of 85 and 16, respectively-as compared to a tissue valve. Following the extended crimping testing, no tears nor surface damage were evident. The results of this study demonstrate the potential of a polymeric TAVR valve to be a viable alternative to tissue-based TAVR valves.

Assessment of neonatal, cord, and adult platelet granule trafficking and secretion.

Despite the transient hyporeactivity of neonatal platelets, full-term neonates do not display a bleeding tendency, suggesting potential compensatory mechanisms which allow for balanced and efficient neonatal hemostasis. This study aimed to utilize small-volume, whole blood platelet functional assays to assess the neonatal platelet response downstream of the hemostatic platelet agonists thrombin and adenosine diphosphate (ADP). Thrombin activates platelets via the protease-activated receptors (PARs) 1 and 4, whereas ADP signals via the receptors P2Y1 and P2Y12 as a positive feedback mediator of platelet activation. We observed that neonatal and cord blood-derived platelets exhibited diminished PAR1-mediated granule secretion and integrin activation relative to adult platelets, correlating to reduced PAR1 expression by neonatal platelets. PAR4-mediated granule secretion was blunted in neonatal platelets, correlating to lower PAR4 expression as compared to adult platelets, while PAR4 mediated GPIIb/IIIa activation was similar between neonatal and adult platelets. Under high shear stress, cord blood-derived platelets yielded similar thrombin generation rates but reduced phosphatidylserine expression as compared to adult platelets. Interestingly, we observed enhanced P2Y1/P2Y12-mediated dense granule trafficking in neonatal platelets relative to adults, although P2Y1/P2Y12 expression in neonatal, cord, and adult platelets were similar, suggesting that neonatal platelets may employ an ADP-mediated positive feedback loop as a potential compensatory mechanism for neonatal platelet hyporeactivity.

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. 29.5 mL/beat). The Evolut PRO reduced the PVL in half compared with the Evolut R (15.7 vs. 28.7 mL/beat). The proposed biomechanical computational model could optimize future TAVR treatment in BAV patients. Graphical abstract.

Prothrombotic activity of cytokine-activated endothelial cells and shear-activated platelets in the setting of ventricular assist device support.

BACKGROUND: We systematically analyzed the synergistic effect of: (i) cytokine-mediated inflammatory activation of endothelial cells (ECs) with and (ii) shear-mediated platelet activation (SMPA) as a potential contributory mechanism to intraventricular thrombus formation in the setting of left ventricular assist device (LVAD) support. METHODS: Intact and shear-activated human platelets were exposed to non-activated and cytokine-activated ECs. To modulate the level of LVAD-related shear activation, platelets were exposed to shear stress patterns of varying magnitude (30, 50, and 70 dynes/cm2, 10 minutes) via a hemodynamic shearing device. ECs were activated via exposure to inflammatory tumor necrosis factor-α (TNF-α 10 and 100 ng/ml, 24 hours), consistent with inflammatory activation recorded in patients on LVAD circulatory support. RESULTS: Adhesivity of shear-activated platelets to ECs was significantly higher than that of intact/unactivated platelets, regardless of the initial activation level (70 dynes/cm2 shear-activated platelets vs intact platelets: +80%, p < 0.001). Importantly, inflammatory activation of ECs amplified platelet prothrombinase activity progressively with increasing shear stress magnitude and TNF-α concentration: thrombin generation of 70 dynes/cm2 shear-activated platelets was 2.6-fold higher after exposure and adhesion to 100 ng/ml TNF-α‒activated ECs (p < 0.0001). CONCLUSIONS: We demonstrated synergistic effect of SMPA and cytokine-mediated EC inflammatory activation to enhance EC‒platelet adhesion and platelet prothrombotic function. These mechanisms may contribute to intraventricular thrombosis in the setting of mechanical circulatory support.

Principles of TAVR valve design, modelling, and testing.

INTRODUCTION: Transcatheter aortic valve replacement (TAVR) has emerged as an effective minimally-invasive alternative to surgical valve replacement in medium- to high-risk, elderly patients with calcific aortic valve disease and severe aortic stenosis. The rapid growth of the TAVR devices market has led to a high variety of designs, each aiming to address persistent complications associated with TAVR valves that may hamper the anticipated expansion of TAVR utility. AREAS COVERED: Here we outline the challenges and the technical demands that TAVR devices need to address for achieving the desired expansion, and review design aspects of selected, latest generation, TAVR valves of both clinically-used and investigational devices. We further review in detail some of the up-to-date modeling and testing approaches for TAVR, both computationally and experimentally, and additionally discuss those as complementary approaches to the ISO 5840-3 standard. A comprehensive survey of the prior and up-to-date literature was conducted to cover the most pertaining issues and challenges that TAVR technology faces. EXPERT COMMENTARY: The expansion of TAVR over SAVR and to new indications seems more promising than ever. With new challenges to come, new TAV design approaches, and materials used, are expected to emerge, and novel testing/modeling methods to be developed.

Realistic Vascular Replicator for TAVR Procedures.

Transcatheter aortic valve replacement (TAVR) is an over-the-wire procedure for treatment of severe aortic stenosis (AS). TAVR valves are conventionally tested using simplified left heart simulators (LHS). While those provide baseline performance reliably, their aortic root geometries are far from the anatomical in situ configuration, often overestimating the valves' performance. We report on a novel benchtop patient-specific arterial replicator designed for testing TAVR and training interventional cardiologists in the procedure. The Replicator is an accurate model of the human upper body vasculature for training physicians in percutaneous interventions. It comprises of fully-automated Windkessel mechanism to recreate physiological flow conditions. Calcified aortic valve models were fabricated and incorporated into the Replicator, then tested for performing TAVR procedure by an experienced cardiologist using the Inovare valve. EOA, pressures, and angiograms were monitored pre- and post-TAVR. A St. Jude mechanical valve was tested as a reference that is less affected by the AS anatomy. Results in the Replicator of both valves were compared to the performance in a commercial ISO-compliant LHS. The AS anatomy in the Replicator resulted in a significant decrease of the TAVR valve performance relative to the simplified LHS, with EOA and transvalvular pressures comparable to clinical data. Minor change was seen in the mechanical valve performance. The Replicator showed to be an effective platform for TAVR testing. Unlike a simplified geometric anatomy LHS, it conservatively provides clinically-relevant outcomes and complement it. The Replicator can be most valuable for testing new valves under challenging patient anatomies, physicians training, and procedural planning.

Microfludic platforms for the evaluation of anti-platelet agent efficacy under hyper-shear conditions associated with ventricular assist devices.

Thrombus formation is a major adverse event affecting patients implanted with ventricular assist devices (VADs). Despite anti-thrombotic drug administration, thrombotic events remain frequent within the first year post-implantation. Platelet activation (PA) is an essential process underling thrombotic adverse events in VAD systems. Indeed, abnormal shear forces, correlating with specific flow trajectories of VADs, are strong agonists mediating PA. To date, the ability to determine efficacy of anti-platelet (AP) agents under shear stress conditions is limited. Here, we present a novel microfluidic platform designed to replicate shear stress patterns of a clinical VAD, and use it to compare the efficacy of two AP agents in vitro. Gel-filtered platelets were incubated with i) acetylsalicylic acid (ASA) and ii) ticagrelor, at two different concentrations (ASA: 125 and 250 µM; ticagrelor: 250 and 500 nM) and were circulated in the VAD-emulating microfluidic platform using a peristaltic pump. GFP was collected after 4 and 52 repetitions of exposure to the VAD shear pattern and tested for shear-mediated PA. ASA significantly inhibited PA only at 2-fold higher concentration (250 µM) than therapeutic dose (125 µM). The effect of ticagrelor was not dependent on drug concentration, and did not show significant inhibition with respect to untreated control. This study demonstrates the potential use of microfluidic platforms as means of testing platelet responsiveness and AP drug efficacy under complex and realistic VAD-like shear stress conditions.

Effect of Balloon-Expandable Transcatheter Aortic Valve Replacement Positioning: A Patient-Specific Numerical Model.

Transcatheter aortic valve replacement (TAVR) has emerged as a life-saving and effective alternative to surgical valve replacement in high-risk, elderly patients with severe calcific aortic stenosis. Despite its early promise, certain limitations and adverse events, such as suboptimal placement and valve migration, have been reported. In the present study, it was aimed to evaluate the effect of various TAVR deployment locations on the procedural outcome by assessing the risk for valve migration. The deployment of a balloon-expandable Edwards SAPIEN valve was simulated via finite element analysis in a patient-specific calcified aortic root, which was reconstructed from CT scans of a retrospective case of valve migration. The deployment location was parametrized in three configurations and the anchorage was quantitatively assessed based on the contact between the stent and the native valve during the deployment and recoil phases. The proximal deployment led to lower contact area between the native leaflets and the stent which poses higher risk for valve migration. The distal and midway positions resulted in comparable outcomes, with the former providing a slightly better anchorage. The approach presented might be used as a predictive tool for procedural planning in order to prevent prosthesis migration and achieve better clinical outcomes.

Fluid-structure interaction modeling of calcific aortic valve disease using patient-specific three-dimensional calcification scans.

Calcific aortic valve disease (CAVD) is characterized by calcification accumulation and thickening of the aortic valve cusps, leading to stenosis. The importance of fluid flow shear stress in the initiation and regulation of CAVD progression is well known and has been studied recently using fluid-structure interaction (FSI) models. While cusp calcifications are three-dimensional (3D) masses, previously published FSI models have represented them as either stiffened or thickened two-dimensional (2D) cusps. This study investigates the hemodynamic effect of these calcifications employing FSI models using 3D patient-specific calcification masses. A new reverse calcification technique (RCT) is used for modeling different stages of calcification growth based on the spatial distribution of calcification density. The RCT is applied to generate the 3D calcification deposits reconstructed from a patient-specific CT scans. Our results showed that consideration of 3D calcification deposits led to both higher fluid shear stresses and unique fluid shear stress distribution on the aortic side of the cusps that may have an impact on the calcification growth rate. However, the flow did not seem to affect the geometry of the calcification during the growth phase.

Hemodynamic and thrombogenic analysis of a trileaflet polymeric valve using a fluid-structure interaction approach.

Surgical valve replacement in patients with severe calcific aortic valve disease using either bioprosthetic or mechanical heart valves is still limited by structural valve deterioration for the former and thrombosis risk mandating anticoagulant therapy for the latter. Prosthetic polymeric heart valves have the potential to overcome the inherent material and design limitations of these valves, but their development is still ongoing. The aim of this study was to characterize the hemodynamics and thrombogenic potential of the Polynova polymeric trileaflet valve prototype using a fluid-structure interaction (FSI) approach. The FSI model replicated experimental conditions of the valve as tested in a left heart simulator. Hemodynamic parameters (transvalvular pressure gradient, flow rate, maximum velocity, and effective orifice area) were compared to assess the validity of the FSI model. The thrombogenic footprint of the polymeric valve was evaluated using a Lagrangian approach to calculate the stress accumulation (SA) values along multiple platelet trajectories and their statistical distribution. In the commissural regions, platelets were exposed to the highest SA values because of highest stress levels combined with local reverse flow patterns and vortices. Stress-loading waveforms from representative trajectories in regions of interest were emulated in our hemodynamic shearing device (HSD). Platelet activity was measured using our platelet activation state (PAS) assay and the results confirmed the higher thrombogenic potential of the commissural hotspots. In conclusion, the proposed method provides an in depth analysis of the hemodynamic and thrombogenic performance of the polymer valve prototype and identifies locations for further design optimization.

Simulation of Transcatheter Aortic Valve Replacement in patient-specific aortic roots: Effect of crimping and positioning on device performance.

Calcific aortic valve disease (CAVD) is a cardiovascular condition that causes the progressive narrowing of the aortic valve (AV) opening, due to the growth of bone-like deposits all over the aortic root (AR). Transcatheter aortic valve replacement (TAVR), a minimally invasive procedure, has recently become the only lifesaving solution for patients that cannot tolerate the standard surgical valve replacement. However, adverse effects, such as AR injury or paravalvular leakage (PVL), may occur as a consequence of a sub-optimal procedure, due to the presence of calcifications in situ. Additionally, the crimping required for delivering the valve via stenting may damage the valve. The aim of the present study is to comparatively assess the crimping mechanics of the commercialized Edwards SAPIEN valve and an alternative polymeric valve (Polynova, Inc) and to evaluate the effect of different TAVR deployment positions using patient-specific numerical models. The optimal deployment location for achieving better patient outcomes was calculated and based on the interactions between the TAVR stent and the native AR. Results demonstrated that the Polynova valve withstands the crimping process better than the SAPIEN valve. Furthermore, deployment simulations showed the role that calcifications deposits may play in the TAVR sub-optimal valve anchoring to the AV wall, leading to the presence of gaps that result in PVL.

Microcalcifications increase coronary vulnerable plaque rupture potential: a patient-based micro-CT fluid-structure interaction study.

Asymptomatic vulnerable plaques (VP) in coronary arteries accounts for significant level of morbidity. Their main risk is associated with their rupture which may prompt fatal heart attacks and strokes. The role of microcalcifications (micro-Ca), embedded in the VP fibrous cap, in the plaque rupture mechanics has been recently established. However, their diminutive size offers a major challenge for studying the VP rupture biomechanics on a patient specific basis. In this study, a highly detailed model was reconstructed from a post-mortem coronary specimen of a patient with observed VP, using high resolution micro-CT which captured the microcalcifications embedded in the fibrous cap. Fluid-structure interaction (FSI) simulations were conducted in the reconstructed model to examine the combined effects of micro-Ca, flow phase lag and plaque material properties on plaque burden and vulnerability. This dynamic fibrous cap stress mapping elucidates the contribution of micro-Ca and flow phase lag VP vulnerability independently. Micro-Ca embedded in the fibrous cap produced increased stresses predicted by previously published analytical model, and corroborated our previous studies. The 'micro-CT to FSI' methodology may offer better diagnostic tools for clinicians, while reducing morbidity and mortality rates for patients with vulnerable plaques and ameliorating the ensuing healthcare costs.

Patient based abdominal aortic aneurysm rupture risk prediction combining clinical visualizing modalities with fluid structure interaction numerical simulations.

Fluid structure interaction (FSI) simulations of patient-specific fusiform non-ruptured and contained ruptured Abdominal Aortic Aneurysm (AAA) geometries were conducted. The goals were: (1) to test the ability of our FSI methodology to predict the location of rupture, by correlating the high wall stress regions with the rupture location, (2) estimate the state of the pathological condition by calculating the ruptured potential index (RPI) of the AAA and (3) predict the disease progression by comparing healthy and pathological aortas.

Patient-based abdominal aortic aneurysm rupture risk prediction with fluid structure interaction modeling.

Elective repair of abdominal aortic aneurysm (AAA) is warranted when the risk of rupture exceeds that of surgery, and is mostly based on the AAA size as a crude rupture predictor. A methodology based on biomechanical considerations for a reliable patient-specific prediction of AAA risk of rupture is presented. Fluid-structure interaction (FSI) simulations conducted in models reconstructed from CT scans of patients who had contained ruptured AAA (rAAA) predicted the rupture location based on mapping of the stresses developing within the aneurysmal wall, additionally showing that a smaller rAAA presented a higher rupture risk. By providing refined means to estimate the risk of rupture, the methodology may have a major impact on diagnostics and treatment of AAA patients.