3D Characterization of the Aortic Valve and Aortic Arch in Bicuspid Aortic Valve Patients.

Patients with bicuspid aortic valve (BAV) commonly have associated aortic stenosis and aortopathy. The geometry of the aortic arch and BAV is not well defined quantitatively, which makes clinical classifications subjective or reliant on limited 2D measurements. The goal of this study was to characterize the 3D geometry of the aortic arch and BAV using objective and quantitative techniques. Pre-TAVR computed tomography angiogram (CTA) in patients with BAV and aortic stenosis (AS) were analyzed (n = 59) by assessing valve commissural angle, presence of a fused region, percent of fusion, and calcium volume. The ascending aorta and aortic arch were reconstructed from patient-specific imaging segmentation to generate a centerline and calculate maximum curvature and maximum area change for the ascending aorta and the descending aorta. Aortic valve commissural angle signified a bimodal distribution suggesting tricuspid-like (≤ 150°, 52.5% of patients) and bicuspid-like (> 150°, 47.5%) morphologies. Tricuspid like was further classified by partial (10.2%) or full (42.4%) fusion, and bicuspid like was further classified into valves with fused region (27.1%) or no fused region (20.3%). Qualitatively, the aortic arch was found to have complex patient-specific variations in its 3D shape with some showing extreme diameter changes and kinks. Quantitatively, subgroups were established using maximum curvature threshold of 0.04 and maximum area change of 30% independently for the ascending and descending aorta. These findings provide insight into the geometric structure of the aortic valve and aortic arch in patients presenting with BAV and AS where 3D characterization allows for quantitative classification of these complex anatomic structures.

Sensitivity of Post-TAVR Hemodynamics to the Distal Aortic Arch Anatomy: A High-Fidelity CFD Study.

PURPOSE: Patient-specific simulations of transcatheter aortic valve (TAV) using computational fluid dynamics (CFD) often rely on assumptions regarding proximal and distal anatomy due to the limited availability of high-resolution imaging away from the TAV site and the primary research focus being near the TAV. However, the influence of these anatomical assumptions on computational efficiency and resulting flow characteristics remains uncertain. This study aimed to investigate the impact of different distal aortic arch anatomies-some of them commonly used in literature-on flow and hemodynamics in the vicinity of the TAV using large eddy simulations (LES). METHODS: Three aortic root anatomical configurations with four representative distal aortic arch types were considered in this study. The arch types included a 90-degree bend, an idealized distal aortic arch anatomy, a clipped version of the idealized distal aortic arch, and an anatomy extruded along the normal of segmented anatomical boundary. Hemodynamic parameters both instantaneous and time-averaged such as Wall Shear Stress (WSS), and Oscillatory Shear Index (OSI) were derived and compared from high-fidelity CFD data. RESULTS: While there were minor differences in flow and hemodynamics across the configurations examined, they were generally not significant within our region of interest i.e., the aortic root. The choice of extension type had a modest impact on TAV hemodynamics, especially in the vicinity of the TAV with variations observed in local flow patterns and parameters near the TAV. However, these differences were not substantial enough to cause significant deviations in the overall flow and hemodynamic characteristics. CONCLUSIONS: The results suggest that under the given configuration and boundary conditions, the type of outflow extension had a modest impact on hemodynamics proximal to the TAV. The findings contribute to a better understanding of flow dynamics in TAV configurations, providing insights for future studies in TAV-related experiments as well as numerical simulations. Additionally, they help mitigate the uncertainties associated with patient-specific geometries, offering increased flexibility in computational modeling.

Reduced Order Modeling for Real-Time Stent Deformation Simulations of Transcatheter Aortic Valve Prostheses.

Computational modeling can be a critical tool to predict deployment behavior for transcatheter aortic valve replacement (TAVR) in patients with aortic stenosis. However, due to the mechanical complexity of the aortic valve and the multiphysics nature of the problem, described by partial differential equations (PDEs), traditional finite element (FE) modeling of TAVR deployment is computationally expensive. In this preliminary study, a PDEs-based reduced order modeling (ROM) framework is introduced for rapidly simulating structural deformation of the Medtronic Evolut R valve stent frame. Using fifteen probing points from an Evolut model with parametrized loads enforced, 105 FE simulations were performed in the so-called offline phase, creating a snapshot library. The library was used in the online phase of the ROM for a new set of applied loads via the proper orthogonal decomposition-Galerkin (POD-Galerkin) approach. Simulations of small radial deformations of the Evolut stent frame were performed and compared to full order model (FOM) solutions. Linear elastic and hyperelastic constitutive models in steady and unsteady regimes were implemented within the ROM. Since the original POD-Galerkin method is formulated for linear problems, specific methods for the nonlinear terms in the hyperelastic case were employed, namely, the Discrete Empirical Interpolation Method. The ROM solutions were in strong agreement with the FOM in all numerical experiments, with a speed-up of at least 92% in CPU Time. This framework serves as a first step toward real-time predictive models for TAVR deployment simulations.

Engineered Extracellular Vesicle-Based Therapies for Valvular Heart Disease.

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

Calcium Fracture and Device Over Expansion in Transcatheter Aortic Valve Replacement for Bicuspid Aortic Valves.

Transcatheter aortic valve replacement (TAVR) in patients with bicuspid aortic valve disease (BAV) has potential risks of under expansion and non-circularity which may compromise long-term durability. This study aims to investigate calcium fracture and balloon over expansion in balloon-expandable TAVs on the stent deformation with the aid of simulation. BAV patients treated with the SAPIEN 3 Ultra with pre- and post-TAVR CTs were analyzed (n = 8). Simulations of the stent deployment were performed (1) with baseline simulation allowing calcium fracture, (2) without allowable calcium fracture and (3) with balloon over expansion (1 mm larger diameter). When compared to post CT, baseline simulations had minimal error in expansion (2.5% waist difference) and circularity (3.0% waist aspect ratio difference). When compared to baseline, calcium fracture had insignificant impact on the expansion (- 0.5% average waist difference) and circularity (- 1.6% average waist aspect ratio difference). Over expansion had significantly larger expansion compared to baseline (15.4% average waist difference) but had insignificant impact on the circularity (- 0.5% waist aspect ratio difference). We conclude that stent deformation can be predicted with minimal error, calcium fracture has small differences on the final stent deformation except in extreme calcified cases, and balloon over expansion expands the waist closer to nominal values.

Transcatheter aortic valve replacement for bicuspid aortic valve disease: does conventional surgery have a future?

Bicuspid aortic valve (BAV) disease is the most common form of congenital heart valve defect. It is associated with aortic stenosis (AS), aortic insufficiency, and aortopathy. Treatment of severe AS requires valve replacement which historically has been performed with surgical aortic valve replacement (SAVR). Recently, transcatheter aortic valve replacement (TAVR) has emerged as a promising alternative. However, increased rates of adverse outcomes following TAVR have been shown in BAV patients with high amounts of calcification. Comparison between TAVR and SAVR in low surgical risk BAV patients in a randomized trial has not been performed and TAVR for BAV long-term performance is unknown due to lack of clinical data. Due to the complexity of BAV anatomies and the significant knowledge gap from the lack of clinical data, SAVR still has many benefits over TAVR in low surgical risk BAV patients. It also remains common for BAV patients to have an aortopathy, which currently can be treated with surgical techniques. This review aims to outline BAV associated diseases and their treatment strategies, the main TAVR adverse outcomes associated with anatomically complex BAV patients, TAVR strategies for mitigating these risks and the current state of cutting-edge 3D printing and computer modeling screening methods that can provide otherwise unobtainable preoperative information during the BAV patient selection process for TAVR.

Effects of MitraClip Therapy on Mitral Flow Patterns and Vortex Formation: An In Vitro Study.

MitraClip transcatheter edge-to-edge repair is used to treat mitral regurgitation (MR). While MR is reduced, diastolic left ventricular flows are altered. An in vitro left heart simulator was used to assess a porcine mitral valve in the native, MR, and MR plus MitraClip cases. Velocity, vorticity, and Reynolds shear stress (RSS) were quantified by particle image velocimetry. Peak velocity increased from 1.20 m/s for native to 1.30 m/s with MR. With MitraClip, two divergent jets of 1.18 and 0.61 m/s emerged. Higher vorticity was observed with MR than native and lessened with MitraClip. MitraClip resulted in shear layer formation and downstream vortex formation. Native RSS decreased from 33 Pa in acceleration to 29 Pa at peak flow, then increased to 31 Pa with deceleration. MR RSS increased from 27 Pa in acceleration to 40 Pa at peak flow to 59 Pa during deceleration. MitraClip RSS increased from 79 Pa in acceleration to 162 Pa during peak flow, then decreased to 45 Pa during deceleration. After MitraClip, two divergent jets of reduced velocity emerged, accompanied by shear layers and recirculation. Chaotic flow developed, resulting in elevated RSS magnitude and coverage. Findings help understand consequences of MitraClip on left ventricular flow dynamics.

Treatment of Bicuspid Aortic Valve Stenosis with TAVR: Filling Knowledge Gaps Towards Reducing Complications.

PURPOSE OF REVIEW: Bicuspid aortic valve (BAV) disease is the most common congenital heart defect worldwide. When severe, symptomatic aortic stenosis ensues, the treatment has increasingly become transcatheter aortic valve replacement (TAVR). The purpose of this review is to identify BAV classification and imaging methods, outline TAVR outcomes in BAV anatomy, and discuss how computational modeling can enhance TAVR treatment in BAV patients. RECENT FINDINGS: TAVR use in BAV patients, when compared to use in tricuspid aortic valves, showed lower device success rate, and there remains no long-term randomized trial data. It has been reported that BAV patients with severe calcification increase the rate of complications. Additionally, the asymmetrical morphology of BAVs often results in asymmetric stent geometries which have implications for increased thrombosis risk and decreased durability. These adverse outcomes are currently very difficult to predict from routine pre-procedural imaging alone. Recently developed patient specific experimental and computational techniques have the potential to assist in filling knowledge gaps in the mechanisms of these complications and provide more information during preclinical planning for better TAVR selection in low surgical risk BAV patients. Efficacy of TAVR for irregular BAV anatomies remains concerning due to the lack of a long-term randomized trial data, their increased rate of short-term complications, and signs that long-term durability could be an issue. More knowledge on identifying which BAV anatomies are at greater risk for these adverse outcomes can potentially improve patient selection for TAVR versus SAVR in low surgical risk BAV patients.

Effect of Left and Right Coronary Flow Waveforms on Aortic Sinus Hemodynamics and Leaflet Shear Stress: Correlation with Calcification Locations.

Coronary flow induces hemodynamic alterations in the aortic sinus region. The objectives of this study are to: (1) investigate the differences among sinus hemodynamics and leaflet wall shear stresses engendered by the left versus right versus non-coronary flow and (2) correlate respective wall shear stresses with leaflet calcification in patients. A left heart simulator flow loop with a tunable coronary circuit provided physiological coronary flow waveforms corresponding to the left coronary cusp case (LCC), right coronary cusp case (RCC), and non-coronary cusp case (NCC). High spatio-temporal resolution particle image velocimetry was conducted to quantify leaflet wall shear stress and sinus vorticity fields and to measure aortic leaflet tip kinematics. Thirty-one patients with severe calcific aortic valve disease were segmented from CT data for the calcific volumes in their respective left, right, and non-coronary cusps. Leaflet tip position during systole shows the RCC has a wider leaflet opening compared to LCC and NCC. Velocity and vorticity fields combined with leaflet position data show that sinus vorticity is diminished (peak ~ 43 s-1) in the LCC while RCC and NCC maintain high vorticity (~ 1200 and ~ 950 s-1 respectively). WSS magnitudes greater than 0.3 Pa show 20 and 81% greater occurrences in the LCC and RCC respectively compared to NCC. Significant differences [X2 (2, n = 31) = 7.31, p = 0.0258] between the calcification levels in each cusp of the patient population. Coronary flow differences between LCC, RCC, and NCC show significant impact on leaflet kinematics and sinus flow hemodynamics. Clinical data correlations of the coronary flow cases indicate the left coronary cusp has a higher likelihood of calcification compared to the right.

Modulation of biomimetic mineralization of collagen by soluble ectodomain of discoidin domain receptor 2.

Collagen fibrils serve as the major template for mineral deposits in both biologically derived and engineered tissues. In recent years certain non-collagenous proteins have been elucidated as important players in differentially modulating intra vs. extra-fibrillar mineralization of collagen. We and others have previously shown that the expression of the collagen receptor, discoidin domain receptor 2 (DDR2) positively correlates with matrix mineralization. The objective of this study was to examine if the ectodomain (ECD) of DDR2 modulates intra versus extra-fibrillar mineralization of collagen independent of cell-signaling. For this purpose, a decellularized collagenous substrate, namely glutaraldehyde fixed porcine pericardium (GFPP) was subjected to biomimetic mineralization protocols. GFPP was incubated in modified simulated body fluid (mSBF) or polymer-induced liquid precursor (PILP) solutions in the presence of recombinant DDR2 ECD (DDR2-Fc) to mediate extra or intra-fibrillar mineralization of collagen. Thermogravimetric analysis revealed that DDR2-Fc increased mineral content in GFPP calcified in mSBF while no significant differences were observed in PILP mediated mineralization. Electron microscopy approaches were used to evaluate the quality and quantity mineral deposits. An increase in the matrix to mineral ratio, frequency of particles and size of mineral deposits was observed in the presence of DDR2-Fc in mSBF. Von Kossa staining and immunohistochemistry analysis of adjacent sections indicated that DDR2-Fc bound to both the matrix and mineral phase of GFPP. Further, DDR2-Fc was found to bind to hydroxyapatite (HAP) particles and enhance the nucleation of mineral deposits in mSBF solutions independent of collagen. Taken together, our results elucidate DDR2 ECD as a novel player in the modulation of extra-fibrillar mineralization of collagen.

Reduction of Pressure Gradient and Turbulence Using Vortex Generators in Prosthetic Heart Valves.

Blood damage and platelet activation are inherent problems with present day bi-leaflet mechanical heart valve designs. Passive flow control through different arrangements of vortex generators (VG) as means of improving pressure gradients and reducing turbulence are investigated. Rectangular VG arrays were mounted on the downstream surfaces of a 23 mm 3D printed mechanical valve. The effect of VGs on the resulting flow structures were assessed under pulsatile physiological flow conditions where high resolution particle image velocimetry measurement was performed. The co-rotating VGs showed lower Reynolds shear stresses and improved pressure gradients (PG) compared with the counter-rotating ones and the no-VG control one (that showed higher turbulence). RSS was found 38.13 ± 0.89, 12.95 ± 0.32, 15.75 ± 0.71, 24.54 ± 0.84 and 16.33 ± 0.58 Pa for the control, co-rotating VGs, 8 counter-rotating VGs, 4 far-spaced VGs and 4 closely-spaced VGs, respectively. PG of 10.45 ± 0.94 mmHg was obtained with co-rotating VGs and the difference was significant compared with the other configurations (control 14.88 ± 0.4 mmHg; 8 counter-rotating VGs 13.76 ± 0.51 mmHg; 4 far-spaced VGs 13.84 ± 0.09 mmHg; and 4 closely-spaced VGs 15.37 ± 0.16 mmHg). Co-rotating VGs for this application induce a more delayed flow separation and a more homogenized and streamlined transition of flow compared with the counter-rotating VGs. Passive flow control techniques deployed on BHMVs is potentially beneficial as significant control of flow at small length scales without inducing large-scale design modifications of the valve.

Hemocompatibility of Super-Repellent surfaces: Current and Future.

Virtually all blood-contacting medical implants and devices initiate immunological events in the form of thrombosis and inflammation. Typically, patients receiving such implants are also given large doses of anticoagulants, which pose a high risk and a high cost to the patient. Thus, the design and development of surfaces with improved hemocompatibility and reduced dependence on anticoagulation treatments is paramount for the success of blood-contacting medical implants and devices. In the past decade, the hemocompatibility of super-repellent surfaces (i.e., surfaces that are extremely repellent to liquids) has been extensively investigated because such surfaces greatly reduce the blood-material contact area, which in turn reduces the area available for protein adsorption and blood cell or platelet adhesion, thereby offering the potential for improved hemocompatibility. In this review, we critically examine the progress made in characterizing the hemocompatibility of super-repellent surfaces, identify the unresolved challenges and highlight the opportunities for future research on developing medical implants and devices with super-repellent surfaces.

An in vitro evaluation of turbulence after transcatheter aortic valve implantation.

BACKGROUND: This study aimed at assessment of post-transcatheter aortic valve (TAV) replacement hemodynamics and turbulence when a same-size SAPIEN 3 (Edwards Lifesciences Corp, Irvine, Calif) and Medtronic Evolut (Minneapolis, Minn) were implanted in a rigid aortic root with physiological dimensions and in a representative root with calcific leaflets obtained from patient computed tomography scans. METHODS: TAV hemodynamics were studied by placing a SAPIEN 3 26-mm and an Evolut 26-mm in rigid aortic roots and representative root with calcific leaflets under physiological conditions. Hemodynamics were assessed using high-fidelity particle image velocimetry and high-speed imaging. Transvalvular pressure gradients (PGs), pinwheeling indices, and Reynolds shear stress (RSS) were calculated. RESULTS: (1) PGs obtained with the Evolut and the SAPIEN 3 were comparable among the different models (10.5 ± 0.15 mm Hg vs 7.76 ± 0.083 mm Hg in the rigid model along with 13.9 ± 0.19 mm Hg vs 5.0 ± 0.09 mm Hg in representative root with calcific leaflets obtained from patient computed tomography scans respectively); (2) more pinwheeling was found in the SAPIEN 3 than the Evolut (0.231 ± 0.057 vs 0.201 ± 0.05 in the representative root with calcific leaflets and 0.366 ± 0.067 vs 0.122 ± 0.045 in the rigid model); (3) higher rates of RSS were found in the Evolut (161.27 ± 3.45 vs 122.84 ± 1.76 Pa in representative root with calcific leaflets and 337.22 ± 7.05 vs 157.91 ± 1.80 Pa in rigid models). More lateral fluctuations were found in representative root with calcific leaflets. CONCLUSIONS: (1) Comparable PGs were found among the TAVs in different models; (2) pinwheeling indices were found to be different between both TAVs; (3) turbulence patterns among both TAVs translated according to RSS were different. Rigid aortic models yield more conservative estimates of turbulence; (4) both TAVs exhibit peak maximal RSS that exceeds platelet activation 100 Pa threshold limit.

Effect of Arched Leaflets and Stent Profile on the Hemodynamics of Tri-Leaflet Flexible Polymeric Heart Valves.

Polymeric heart valves (PHV) can be engineered to serve as alternatives for existing prosthetic valves due to higher durability and hemodynamics similar to bioprosthetic valves. The purpose of this study is to evaluate the effect of geometry on PHVs coaptation and hemodynamic performance. The two geometric factors considered are stent profile and leaflet arch length, which were varied across six valve configurations. Three models were created with height to diameter ratio of 0.6, 0.7, and 0.88. The other three models were designed by altering arch height to stent diameter ratio, to be 0, 0.081, and 0.116. Particle image velocimetry experiments were conducted on each PHV to characterize velocity, vorticity, turbulent characteristics, effective orifice area, and regurgitant fraction. This study revealed that the presence of arches as well as higher stent profile reduced regurgitant flow down to 5%, while peak systole downstream velocity reduced to 58% and Reynolds Shear Stress values reduced 40%. Further, earlier reattachment of the forward flow jet was observed in PHVs with leaflet arches. These findings indicate that although both geometric factors help diminish the commissural gap during diastole, leaflet arches induce a larger jet opening, yielding to earlier flow reattachment and lower energy dissipation.

Hemodynamic Performance and Thrombogenic Properties of a Superhydrophobic Bileaflet Mechanical Heart Valve.

In this study, we explore how blood-material interactions and hemodynamics are impacted by rendering a clinical quality 25 mm St. Jude Medical Bileaflet mechanical heart valve (BMHV) superhydrophobic (SH) with the aim of reducing thrombo-embolic complications associated with BMHVs. Basic cell adhesion is evaluated to assess blood-material interactions, while hemodynamic performance is analyzed with and without the SH coating. Results show that a SH coating with a receding contact angle (CA) of 160° strikingly eliminates platelet and leukocyte adhesion to the surface. Alternatively, many platelets attach to and activate on pyrolytic carbon (receding CA = 47), the base material for BMHVs. We further show that the performance index increases by 2.5% for coated valve relative to an uncoated valve, with a maximum possible improved performance of 5%. Both valves exhibit instantaneous shear stress below 10 N/m2 and Reynolds Shear Stress below 100 N/m2. Therefore, a SH BMHV has the potential to relax the requirement for antiplatelet and anticoagulant drug regimens typically required for patients receiving MHVs by minimizing blood-material interactions, while having a minimal impact on hemodynamics. We show for the first time that SH-coated surfaces may be a promising direction to minimize thrombotic complications in complex devices such as heart valves.

On the Mechanics of Transcatheter Aortic Valve Replacement.

Transcatheter aortic valves (TAVs) represent the latest advances in prosthetic heart valve technology. TAVs are truly transformational as they bring the benefit of heart valve replacement to patients that would otherwise not be operated on. Nevertheless, like any new device technology, the high expectations are dampened with growing concerns arising from frequent complications that develop in patients, indicating that the technology is far from being mature. Some of the most common complications that plague current TAV devices include malpositioning, crimp-induced leaflet damage, paravalvular leak, thrombosis, conduction abnormalities and prosthesis-patient mismatch. In this article, we provide an in-depth review of the current state-of-the-art pertaining the mechanics of TAVs while highlighting various studies guiding clinicians, regulatory agencies, and next-generation device designers.

Hemocompatibility of Superhemophobic Titania Surfaces.

The hemocompatibility of superhemophobic surfaces is investigated and compared with that of hemophobic surfaces and hemophilic surfaces. This analysis indicates that only those superhemophobic surfaces with a robust Cassie-Baxter state display significantly lower platelet adhesion and activation. It is envisioned that the understanding gained through this work will lead to the fabrication of improved hemocompatible, superhemophobic medical implants.