Platelet Biorheology and Mechanobiology in Thrombosis and Hemostasis: Perspectives from Multiscale Computation.

Thrombosis is the pathological clot formation under abnormal hemodynamic conditions, which can result in vascular obstruction, causing ischemic strokes and myocardial infarction. Thrombus growth under moderate to low shear (<1000 s-1) relies on platelet activation and coagulation. Thrombosis at elevated high shear rates (>10,000 s-1) is predominantly driven by unactivated platelet binding and aggregating mediated by von Willebrand factor (VWF), while platelet activation and coagulation are secondary in supporting and reinforcing the thrombus. Given the molecular and cellular level information it can access, multiscale computational modeling informed by biology can provide new pathophysiological mechanisms that are otherwise not accessible experimentally, holding promise for novel first-principle-based therapeutics. In this review, we summarize the key aspects of platelet biorheology and mechanobiology, focusing on the molecular and cellular scale events and how they build up to thrombosis through platelet adhesion and aggregation in the presence or absence of platelet activation. In particular, we highlight recent advancements in multiscale modeling of platelet biorheology and mechanobiology and how they can lead to the better prediction and quantification of thrombus formation, exemplifying the exciting paradigm of digital medicine.

Shear-Mediated Platelet Microparticles Demonstrate Phenotypic Heterogeneity as to Morphology, Receptor Distribution, and Hemostatic Function.

Implantable Cardiovascular Therapeutic Devices (CTD), while lifesaving, impart supraphysiologic shear stress to platelets, resulting in thrombotic and bleeding coagulopathy. We previously demonstrated that shear-mediated platelet dysfunction is associated with downregulation of platelet GPIb-IX-V and αIIbß3 receptors via generation of Platelet-Derived MicroParticles (PDMPs). Here, we test the hypothesis that sheared PDMPs manifest phenotypical heterogeneity of morphology and receptor surface expression and modulate platelet hemostatic function. Human gel-filtered platelets were exposed to continuous shear stress. Alterations of platelet morphology were visualized using transmission electron microscopy. Surface expression of platelet receptors and PDMP generation were quantified by flow cytometry. Thrombin generation was quantified spectrophotometrically, and platelet aggregation was measured by optical aggregometry. Shear stress promotes notable alterations in platelet morphology and ejection of distinctive types of PDMPs. Shear-mediated microvesiculation is associated with the remodeling of platelet receptors, with PDMPs expressing significantly higher levels of adhesion receptors (αIIbß3, GPIX, PECAM-1, P-selectin, and PSGL-1) and agonist receptors (P2Y12 and PAR1). Sheared PDMPs promote thrombin generation and inhibit platelet aggregation induced by collagen and ADP. Sheared PDMPs demonstrate phenotypic heterogeneity as to morphology and defined patterns of surface receptors and impose a bidirectional effect on platelet hemostatic function. PDMP heterogeneity suggests that a range of mechanisms are operative in the microvesiculation process, contributing to CTD coagulopathy and posing opportunities for therapeutic manipulation.

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

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A computational framework for post-TAVR cardiac conduction abnormality (CCA) risk assessment in patient-specific anatomy.

BACKGROUND: Cardiac conduction abnormality (CCA)- one of the major persistent complications associated with transcatheter aortic valve replacement (TAVR) may lead to permanent pacemaker implantation. Localized stresses exerted by the device frame on the membranous septum (MS) which lies between the aortic annulus and the bundle of His, may disturb the cardiac conduction and cause the resultant CCA. We hypothesize that the area-weighted average maximum principal logarithmic strain (AMPLS) in the MS region can predict the risk of CCA following TAVR. METHODS: Rigorous finite element-based analysis was conducted in two patients (Balloon expandable TAVR recipients) to assess post-TAVR CCA risk. Following the procedure one of the patients required permanent pacemaker (PPM) implantation while the other did not (control case). Patient-specific aortic root was modeled, MS was identified from the CT image, and the TAVR deployment was simulated. Mechanical factors in the MS region such as logarithmic strain, contact force, contact pressure, contact pressure index (CPI) and their time history during the TAVR deployment; and anatomical factors such as MS length, implantation depth, were analyzed. RESULTS: Maximum AMPLS (0.47 and 0.37, respectively), contact force (0.92 N and 0.72 N, respectively), and CPI (3.99 and 2.86, respectively) in the MS region were significantly elevated in the PPM patient as compared to control patient. CONCLUSION: Elevated stresses generated by TAVR devices during deployment appear to correlate with CCA risk, with AMPLS in the MS region emerging as a strong predictor that could be used for preprocedural planning in order to minimize CCA risk.

Visions of TAVR Future: Development and Optimization of a Second Generation Novel Polymeric TAVR.

Tissue-based transcatheter aortic valve (AV) replacement (TAVR) devices have been a breakthrough approach for treating aortic valve stenosis. However, with the expansion of TAVR to younger and lower risk patients, issues of long-term durability and thrombosis persist. Recent advances in polymeric valve technology facilitate designing more durable valves with minimal in vivo adverse reactions. We introduce our second-generation polymeric transcatheter aortic valve (TAV) device, designed and optimized to address these issues. We present the optimization process of the device, wherein each aspect of device deployment and functionality was optimized for performance, including unique considerations of polymeric technologies for reducing the volume of the polymer material for lower crimped delivery profiles. The stent frame was optimized to generate larger radial forces with lower material volumes, securing robust deployment and anchoring. The leaflet shape, combined with varying leaflets thickness, was optimized for reducing the flexural cyclic stresses and the valve's hydrodynamics. Our first-generation polymeric device already demonstrated that its hydrodynamic performance meets and exceeds tissue devices for both ISO standard and patient-specific in vitro scenarios. The valve already reached 900 × 106 cycles of accelerated durability testing, equivalent to over 20 years in a patient. The optimization framework and technology led to the second generation of polymeric TAV design- currently undergoing in vitro hydrodynamic testing and following in vivo animal trials. As TAVR use is rapidly expanding, our rigorous bio-engineering optimization methodology and advanced polymer technology serve to establish polymeric TAV technology as a viable alternative to the challenges facing existing tissue-based TAV technology.

Patient-specific in vitro testing for evaluating TAVR clinical performance-A complementary approach to current ISO standard testing.

Following in vitro tests established for surgical prosthetic heart valves, transcatheter aortic valves (TAV) are similarly tested in idealized geometries-excluding effects that may hamper TAVR performance in situ. Testing in vitro in pulse duplicator systems that incorporated patient-specific replicas would enhance the testing veracity by bringing it closer to the clinical scenario. To that end we compare TAV hemodynamic performance tested in idealized geometries according to the ISO standard (baseline performance) to that obtained by testing the TAVs following deployment in patient-specific replicas. Balloon-expandable (n = 2) and self-expandable (n = 3) TAVs were tested in an idealized geometry in mock-circulation system (following ISO 5840-3 guidelines) and compared to the measurements in a dedicated mock-circulation system adapted for the five patient-specific replicas. Patient-specific deployments resulted in a decline in performance as compared to the baseline idealized testing, as well as a variation in performance that depended on the design features of each device that was further correlated with the radial expansion and eccentricity of the deployed TAV stent (obtained with CT-scans of the deployed valves). By excluding the deployment effects in irregular geometries, the current idealized ISO testing is limited to characterize the baseline device performance. Utilizing patient-specific anatomic contours provides performance indicators under more stringent conditions likely encountered in vivo. It has the potential to enhance testing and development complementary to the ISO standard, for improved TAV safety and effectiveness.

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.

Circulatory loop design and components introduce artifacts impacting in vitro evaluation of ventricular assist device thrombogenicity: A call for caution.

Mechanical circulatory support (MCS) devices continue to be hampered by thrombotic adverse events (AEs), a consequence of device-imparted supraphysiologic shear stresses, leading to shear-mediated platelet activation (SMPA). In advancing MCS devices from design to clinical use, in vitro circulatory loops containing the device under development and testing are utilized as a means of assessing device thrombogenicity. Physical characteristics of these test circulatory loops may also contribute to inadvertent platelet activation through imparted shear stress, adding inadvertent error in evaluating MCS device thrombogenicity. While investigators normally control for the effect of a loop, inadvertent addition of what are considered innocuous connectors may impact test results. Here, we tested the effect of common, additive components of in vitro circulatory test loops, that is, connectors and loop geometry, as to their additive contribution to shear stress via both in silico and in vitro models. A series of test circulatory loops containing a ventricular assist device (VAD) with differing constituent components, were established in silico including: loops with 0~5 Luer connectors, a loop with a T-connector creating 90° angulation, and a loop with 90° angulation. Computational fluid dynamics (CFD) simulations were performed using a k - ω shear stress transport turbulence model to platelet activation index (PAI) based on a power law model. VAD-operated loops replicating in silico designs were assembled in vitro and gel-filtered human platelets were recirculated within (1 hour) and SMPA was determined. CFD simulations demonstrated high shear being introduced at non-smooth regions such as edge-connector boundaries, tubing, and at Luer holes. Noticeable peaks' shifts of scalar shear stress (sss) distributions toward high shear-region existed with increasing loop complexity. Platelet activation also increased with increasing shear exposure time, being statistically higher when platelets were exposed to connector-employed loop designs. The extent of platelet activation in vitro could be successfully predicted by CFD simulations. Loops employing additional components (non-physiological flow pattern connectors) resulted in higher PAI. Loops with more components (5-connector loop and 90° T-connector) showed 63% and 128% higher platelet activation levels, respectively, versus those with fewer (0-connector (P = .023) and a 90° heat-bend loop (P = .0041). Our results underscore the importance of careful consideration of all component elements, and suggest the need for standardization in designing in vitro circulatory loops for MCS device evaluation to avoid inadvertent additive SMPA during device evaluation, confounding overall results. Specifically, we caution on the use and inadvertent introduction of additional connectors, ports, and other shear-generating elements which introduce artifact, clouding primary device evaluation via introduction of additive SMPA.

Design Effect of Metallic (Durable) and Polymeric (Resorbable) Stents on Blood Flow and Platelet Activation.

Bioresorbable vascular scaffolds (BVS) provide transient vessel support for occluded coronary arteries while resorbing over time, potentially allowing vessel restoration approximating the native, healthy state. Clinical trials indicate that the Absorb BVS (Abbott Vascular, Santa Clara, CA) performance was similar to that of the Xience metallic drug-eluting stent (DES), with low long-term complications rates. However, when under-deployed in very small vessels (diameter < 2.25 mm), the thrombosis rate of BVS was higher, possibly due to the effect of strut thickness on the hemodynamics (157 µm BVS vs. 81 µm DES). This study aims to determine the influence of BVS design in vessels of varying diameter on the potential platelet activation. Sixteen computational fluid dynamics models of vessels of varying diameter (1.8-3.0 mm), strut thickness (81-157 µm), and BVS/DES designs were compared. Platelet stress accumulation (SA), a metric for the activation potential, was calculated along platelet flow trajectories and their probability distribution was compared. The models were consistent with clinical observations, indicating that devices deployed in very small vessels exhibited increased probability for platelet activity as compared to the same devices deployed in nominal sized vessels. Deployment, although with residual stenosis, increased probability for higher SA than in similar diameter straight vessels. Reducing BVS struts thickness while maintaining their pattern improved performance closer to that of DES. Our findings highlight the importance of appropriate vessel sizing and deployment technique for BVS, and may help designing future BVS with thinner struts, ultimately improving performance in very small vessels.

Comparative Fluid-Structure Interaction Analysis of Polymeric Transcatheter and Surgical Aortic Valves' Hemodynamics and Structural Mechanics.

Transcatheter aortic valve replacement (TAVR) has emerged as an effective alternative to conventional surgical aortic valve replacement (SAVR) in high-risk elderly patients with calcified aortic valve disease. All currently FDA-approved TAVR devices use tissue valves that were adapted to but not specifically designed for TAVR use. Emerging clinical evidence indicates that these valves may get damaged during crimping and deployment- leading to valvular calcification, thrombotic complications, and limited durability. This impedes the expected expansion of TAVR to lower-risk and younger patients. Viable polymeric valves have the potential to overcome such limitations. We have developed a polymeric SAVR valve, which was optimized to reduce leaflet stresses and offer a thromboresistance profile similar to that of a tissue valve. This study compares the polymeric SAVR valve's hemodynamic performance and mechanical stresses to a new version of the valve- specifically designed for TAVR. Fluid-structure interaction (FSI) models were utilized and the valves' hemodynamics, flexural stresses, strains, orifice area, and wall shear stresses were compared. The TAVR valve had 42% larger opening area and 27% higher flow rate versus the SAVR valve, while wall shear stress distribution and mechanical stress magnitudes were of the same order, demonstrating the enhanced performance of the TAVR valve prototype. The TAVR valve FSI simulation and Vivitro pulse duplicator experiments were compared in terms of the leaflets' kinematics and the effective orifice area. The numerical methodology presented can be further used as a predictive tool for valve design optimization for enhanced hemodynamics and durability.

Repetitive Hypershear Activates and Sensitizes Platelets in a Dose-Dependent Manner.

Implantation of mechanical circulatory support (MCS) devices-ventricular assist devices and the total artificial heart-has emerged as a vital therapy for advanced and end-stage heart failure. Unfortunately, MCS patients face the requirement of life-long antiplatelet and anticoagulant therapy to combat thrombotic complications resulting from the dynamic and supraphysiologic shear stress conditions associated with such devices, whose effect on platelet activation is poorly understood. We developed a syringe-capillary viscometer-the "platelet hammer"-that repeatedly exposed platelets to average shear stresses up to 1000 dyne/cm(2) for as short as 25 ms. Platelet activation state was measured using a modified prothrombinase assay, with morphological changes analyzed using scanning electron microscopy. We observed an increase in platelet activation state and post-high shear platelet activation rate, or sensitization, with an increase in stress accumulation (SA), the product of shear stress and exposure time. A significant increase in platelet activation state was observed beyond an SA of 1500 dyne-s/cm(2) , with a marked increase in pseudopod length visible beyond an SA of 1000 dyne-s/cm(2) . Utility of the platelet hammer extends to studies of other shear-dependent pathologies, and may assist development of approaches to enhance the safety and effectiveness of MCS devices and objective antithrombotic pharmacotherapy management.

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.

Scalability Test of Multiscale Fluid-Platelet Model for Three Top Supercomputers.

We have tested the scalability of three supercomputers: the Tianhe-2, Stampede and CS-Storm with multiscale fluid-platelet simulations, in which a highly-resolved and efficient numerical model for nanoscale biophysics of platelets in microscale viscous biofluids is considered. Three experiments involving varying problem sizes were performed: Exp-S: 680,718-particle single-platelet; Exp-M: 2,722,872-particle 4-platelet; and Exp-L: 10,891,488-particle 16-platelet. Our implementations of multiple time-stepping (MTS) algorithm improved the performance of single time-stepping (STS) in all experiments. Using MTS, our model achieved the following simulation rates: 12.5, 25.0, 35.5 µs/day for Exp-S and 9.09, 6.25, 14.29 µs/day for Exp-M on Tianhe-2, CS-Storm 16-K80 and Stampede K20. The best rate for Exp-L was 6.25 µs/day for Stampede. Utilizing current advanced HPC resources, the simulation rates achieved by our algorithms bring within reach performing complex multiscale simulations for solving vexing problems at the interface of biology and engineering, such as thrombosis in blood flow which combines millisecond-scale hematology with microscale blood flow at resolutions of micro-to-nanoscale cellular components of platelets. This study of testing the performance characteristics of supercomputers with advanced computational algorithms that offer optimal trade-off to achieve enhanced computational performance serves to demonstrate that such simulations are feasible with currently available HPC resources.

Hemolysate-mediated platelet aggregation: an additional risk mechanism contributing to thrombosis of continuous flow ventricular assist devices.

Despite the clinical success and growth in the utilization of continuous flow ventricular assist devices (cfVADs) for the treatment of advanced heart failure, hemolysis and thrombosis remain major limitations. Inadequate and/or ineffective anticoagulation regimens, combined with high pump speed and non-physiological flow patterns, can result in hemolysis which often is accompanied by pump thrombosis. An unexpected increase in cfVADs thrombosis was reported by multiple major VAD implanting centers in 2014, highlighting the association of hemolysis and a rise in lactate dehydrogenase (LDH) presaging thrombotic events. It is well established that thrombotic complications arise from the abnormal shear stresses generated by cfVADs. What remains unknown is the link between cfVAD-associated hemolysis and pump thrombosis. Can hemolysis of red blood cells (RBCs) contribute to platelet aggregation, thereby, facilitating prothrombotic complications in cfVADs? Herein, we examine the effect of RBC-hemolysate and selected major constituents, i.e., lactate dehydrogenase (LDH) and plasma free hemoglobin (pHb) on platelet aggregation, utilizing electrical resistance aggregometry. Our hypothesis is that elements of RBCs, released as a result of shear-mediated hemolysis, will contribute to platelet aggregation. We show that RBC hemolysate and pHb, but not LDH, are direct contributors to platelet aggregation, posing an additional risk mechanism for cfVAD thrombosis.

Microfluidic emulation of mechanical circulatory support device shear-mediated platelet activation.

Thrombosis of ventricular assist devices (VADs) compromises their performance, with associated risks of systemic embolization, stroke, pump stop and possible death. Anti-thrombotic (AT) drugs, utilized to limit thrombosis, are largely dosed empirically, with limited testing of their efficacy. Further, such testing, if performed, typically examines efficacy under static conditions, which is not reflective of actual shear-mediated flow. Here we adopted our previously developed Device Thrombogenicity Emulation methodology to design microfluidic platforms able to emulate representative shear stress profiles of mechanical circulatory support (MCS) devices. Our long-term goal is to utilize these systems for point-of-care (POC) personalized testing of AT efficacy under specific, individual shear profiles. First, we designed different types of microfluidic channels able to replicate sample shear stress patterns observed in MCS devices. Second, we explored the flexibility of microfluidic technology in generating dynamic shear stress profiles by modulating the geometrical features of the channels. Finally, we designed microfluidic channel systems able to emulate the shear stress profiles of two commercial VADs. From CFD analyses, the VAD-emulating microfluidic systems were able to replicate the main characteristics of the shear stress waveforms of the macroscale VADs (i.e., shear stress peaks and duration). Our results establish the basis for development of a lab-on-chip POC system able to perform device-specific and patient-specific platelet activation state assays.

Comparative efficacy of in vitro and in vivo metabolized aspirin in the DeBakey ventricular assist device.

Ventricular assist devices (VADs) are implanted in patients with end-stage heart failure to provide both short- and long-term hemodynamic support. Unfortunately, bleeding and thromboembolic complications due to the severely disturbed, dynamic flow conditions generated within these devices require complex, long-term antiplatelet and anticoagulant therapy. While several studies have examined the effectiveness of one such agent, aspirin, under flow conditions, data comparing the efficacy of in vitro and in vivo metabolized aspirin is lacking. Two sets of studies were conducted in vitro with purified human platelets circulating for 30 min in a flow loop containing the DeBakey VAD (MicroMed Cardiovascular, Houston, TX, USA): (a) 20 µM aspirin was added exogenously in vitro to platelets isolated from aspirin-free subjects, and (b) platelets were obtained from donors 2 h (n = 14) and 20 h (n = 13) after ingestion of 1,000 mg aspirin. Near real-time platelet activation state (PAS) was measured with a modified prothrombinase-based assay. Platelets exposed to aspirin in vitro and in vivo (metabolized) showed 28.2 and 25.3 % reduction in platelet activation rate, respectively, compared to untreated controls. Our results demonstrate that in vitro treatment with antiplatelet drugs such as aspirin is as effective as in vivo metabolized aspirin in testing the effect of reducing shear-induced platelet activation in the VAD. Using the PAS assay provides a practical in vitro alternative to in vivo testing of antiplatelet efficacy, as well as for testing the thrombogenic performance of devices during their research and development.

Thromboresistance comparison of the HeartMate II ventricular assist device with the device thrombogenicity emulation- optimized HeartAssist 5 VAD.

Approximately 7.5 × 106 patients in the US currently suffer from end-stage heart failure. The FDA has recently approved the designations of the Thoratec HeartMate II ventricular assist device (VAD) for both bridge-to-transplant and destination therapy (DT) due to its mechanical durability and improved hemodynamics. However, incidence of pump thrombosis and thromboembolic events remains high, and the life-long complex pharmacological regimens are mandatory in its VAD recipients. We have previously successfully applied our device thrombogenicity emulation (DTE) methodology for optimizing device thromboresistance to the Micromed Debakey VAD, and demonstrated that optimizing device features implicated in exposing blood to elevated shear stresses and exposure times significantly reduces shear-induced platelet activation and significantly improves the device thromboresistance. In the present study, we compared the thrombogenicity of the FDA-approved HeartMate II VAD with the DTE-optimized Debakey VAD (now labeled HeartAssist 5). With quantitative probability density functions of the stress accumulation along large number of platelet trajectories within each device which were extracted from numerical flow simulations in each device, and through measurements of platelet activation rates in recirculation flow loops, we specifically show that: (a) Platelets flowing through the HeartAssist 5 are exposed to significantly lower stress accumulation that lead to platelet activation than the HeartMate II, especially at the impeller-shroud gap regions (b) Thrombus formation patterns observed in the HeartMate II are absent in the HeartAssist 5 (c) Platelet activation rates (PAR) measured in vitro with the VADs mounted in recirculation flow-loops show a 2.5-fold significantly higher PAR value for the HeartMate II. This head to head thrombogenic performance comparative study of the two VADs, one optimized with the DTE methodology and one FDA-approved, demonstrates the efficacy of the DTE methodology for drastically reducing the device thrombogenic potential, validating the need for a robust in silico/in vitro optimization methodology for improving cardiovascular devices thromboresistance.

Assessing Post-TAVR Cardiac Conduction Abnormalities Risk Using a Digital Twin of a Beating Heart.

Transcatheter aortic valve replacement (TAVR) has rapidly displaced surgical aortic valve replacement (SAVR). However, certain post-TAVR complications persist, with cardiac conduction abnormalities (CCA) being one of the major ones. The elevated pressure exerted by the TAVR stent onto the conduction fibers situated between the aortic annulus and the His bundle, in proximity to the atrioventricular (AV) node, may disrupt the cardiac conduction leading to the emergence of CCA. In his study, an in-silico framework was developed to assess the CCA risk, incorporating the effect of a dynamic beating heart and pre-procedural parameters such as implantation depth and preexisting cardiac asynchrony in the new onset of post-TAVR CCA. A self-expandable TAVR device deployment was simulated inside an electro-mechanically coupled beating heart model in five patient scenarios, including three implantation depths, and two preexisting cardiac asynchronies: (i) a right bundle branch block (RBBB) and (ii) a left bundle branch block (LBBB). Subsequently, several biomechanical parameters were analyzed to assess the post-TAVR CCA risk. The results manifested a lower cumulative contact pressure on the conduction fibers following TAVR for aortic deployment (0.018 MPa) compared to baseline (0.29 MPa) and ventricular deployment (0.52 MPa). Notably, the preexisting RBBB demonstrated a higher cumulative contact pressure (0.34 MPa) compared to the baseline and preexisting LBBB (0.25 MPa). Deeper implantation and preexisting RBBB cause higher stresses and contact pressure on the conduction fibers leading to an increased risk of post-TAVR CCA. Conversely, implantation above the MS landmark and preexisting LBBB reduces the risk.

Thrombogenic Risk Assessment of Transcatheter Prosthetic Heart Valves Using a Fluid-Structure Interaction Approach.

Background and Objective: Prosthetic heart valve interventions such as TAVR have surged over the past decade, but the associated complication of long-term, life-threatening thrombotic events continues to undermine patient outcomes. Thus, improving thrombogenic risk analysis of TAVR devices is crucial. In vitro studies for thrombogenicity are typically difficult to perform. However, revised ISO testing standards include computational testing for thrombogenic risk assessment of cardiovascular implants. We present a fluid-structure interaction (FSI) approach for assessing thrombogenic risk of prosthetic heart valves. Methods: An FSI framework was implemented via the incompressible computational fluid dynamics multi-physics solver of the Ansys LS-DYNA software. The numerical modeling approach for flow analysis was validated by comparing the derived flow rate of the 29-mm CoreValve device from benchtop testing and orifice areas of commercial TAVR valves in the literature to in silico results. Thrombogenic risk was analyzed by computing stress accumulation (SA) on virtual platelets seeded in the flow fields via Ansys EnSight. The integrated FSI-thrombogenicity methodology was subsequently employed to examine hemodynamics and thrombogenic risk of TAVR devices with two approaches: 1) engineering optimization and 2) clinical assessment. Results: The simulated effective orifice areas of the commercial devices were in the range reported in the literature. The flow rates from the in vitro flow testing matched well with the in silico results. The approach was used to analyze the effect of various TAVR leaflet designs on hemodynamics. Platelets experienced different magnitudes of SA along their trajectories as they flowed past each design. Post-TAVR deployment hemodynamics in patient-specific bicuspid aortic valve anatomies revealed varying degrees of thrombogenic risk for these patients, despite being clinically defined as "mild" paravalvular leak. Conclusions: Our methodology can be used to improve the thromboresistance of prosthetic valves from the initial design stage to the clinic. It allows for unparalleled optimization of devices, uncovering key TAVR leaflet design parameters that can be used to mitigate thrombogenic risk, in addition to patient-specific modeling to evaluate device performance. This work demonstrates the utility of advanced in silico analysis of TAVR devices that can be utilized for thrombogenic risk assessment of other blood recirculating devices.