Targeted Rapamycin Delivery via Magnetic Nanoparticles to Address Stenosis in a 3D Bioprinted in Vitro Model of Pulmonary Veins.

Vascular cell overgrowth and lumen size reduction in pulmonary vein stenosis (PVS) can result in elevated PV pressure, pulmonary hypertension, cardiac failure, and death. Administration of chemotherapies such as rapamycin have shown promise by inhibiting the vascular cell proliferation; yet clinical success is limited due to complications such as restenosis and off-target effects. The lack of in vitro models to recapitulate the complex pathophysiology of PVS has hindered the identification of disease mechanisms and therapies. This study integrated 3D bioprinting, functional nanoparticles, and perfusion bioreactors to develop a novel in vitro model of PVS. Bioprinted bifurcated PV constructs are seeded with endothelial cells (ECs) and perfused, demonstrating the formation of a uniform and viable endothelium. Computational modeling identified the bifurcation point at high risk of EC overgrowth. Application of an external magnetic field enabled targeting of the rapamycin-loaded superparamagnetic iron oxide nanoparticles at the bifurcation site, leading to a significant reduction in EC proliferation with no adverse side effects. These results establish a 3D bioprinted in vitro model to study PV homeostasis and diseases, offering the potential for increased throughput, tunability, and patient specificity, to test new or more effective therapies for PVS and other vascular diseases.

Predicting pressure gradient using artificial intelligence for transcatheter aortic valve replacement.

Objective: After transcatheter aortic valve replacement, the mean transvalvular pressure gradient indicates the effectiveness of the therapy. The objective is to develop artificial intelligence to predict the post-transcatheter aortic valve replacement aortic valve pressure gradient and aortic valve area from preprocedural echocardiography and computed tomography data. Methods: A retrospective study was conducted on patients who underwent transcatheter aortic valve replacement due to aortic valve stenosis. A total of 1091 patients were analyzed for pressure gradient predictions (mean age 76.8 ± 9.2 years, 57.8% male), and 1063 patients were analyzed for aortic valve area predictions (mean age 76.7 ± 9.3 years, 57.2% male). An artificial intelligence learning model was trained (training: n = 663 patients, validation: n = 206 patients) and tested (testing: n = 222 patients) to predict pressure gradient, and a separate artificial intelligence learning model was trained (training: n = 640 patients, validation: n = 218 patients) and tested (testing: n = 205 patients) for predicting aortic valve area. Results: The mean absolute error for pressure gradient and aortic valve area predictions was 3.0 mm Hg and 0.45 cm2, respectively. Valve sheath size, body surface area, and age were determined to be the top 3 predictors for pressure gradient, and valve sheath size, left ventricular ejection fraction, and aortic annulus mean diameter were identified to be the top 3 predictors of post-transcatheter aortic valve replacement aortic valve area. A training dataset size of more than 500 patients demonstrated good robustness of the artificial intelligence models for pressure gradient and aortic valve area. Conclusions: The artificial intelligence-based algorithm has demonstrated potential in predicting post-transcatheter aortic valve replacement transvalvular pressure gradient predictions for patients with aortic valve stenosis. Further studies are necessary to differentiate pressure gradient between valve types.

Differential Impact of Blood Pressure Control Targets on Epicardial Coronary Flow After Transcatheter Aortic Valve Replacement.

Background: The cause for the association between increased cardiovascular mortality rates and lower blood pressure (BP) after aortic valve replacement (AVR) is unclear. This study aims to assess how the epicardial coronary flow (ECF) after AVR varies as BP levels are changed in the presence of a right coronary lesion. Methods: The hemodynamics of a 3D printed aortic root model with a SAPIEN 3 26 deployed were evaluated in an in vitro left heart simulator under a range of varying systolic blood pressure (SBP) and diastolic blood pressure (DBP). ECF and the flow ratio index were calculated. Flow index value <0.8 was considered a threshold for ischemia. Results: As SBP decreased, the average ECF decreased below the physiological coronary minimum at 120 mmHg. As DBP decreased, the average ECF was still maintained above the physiological minimum. The flow ratio index was >0.9 for SBP ≥130 mmHg. However, at an SBP of 120 mmHg, the flow ratio was 0.63 (p ≤ 0.0055). With decreasing DBP, no BP condition yielded a flow ratio index that was less than 0.91. Conclusions: Reducing BP to the current recommended levels assigned for the general population after AVR in the presence of coronary artery disease may require reconsideration of levels and treatment priority. Additional studies are needed to fully understand the changes in ECF dynamics after AVR in the presence and absence of coronary artery disease.

Development of Novel Sutureless Balloon Expandable Fetal Heart Valve Device Using Absorbable Polycaprolactone Leaflets.

Congenital heart disease (CHD) accounts for nearly one-third of all congenital defects, and patients often require repeated heart valve replacements throughout their lives, due to failed surgical repairs and lack of durability of bioprosthetic valve implants. This objective of this study is to develop and in vitro test a fetal transcatheter pulmonary valve replacement (FTPVR) using sutureless techniques to attach leaflets, as an option to correct congenital defects such as pulmonary atresia with intact ventricular septum (PA/IVS), in utero. A balloon expandable design was analyzed using computational simulations to identify areas of failure. Five manufactured valves were assembled using the unique sutureless approach and tested in the fetal right heart simulator (FRHS) to evaluate hemodynamic characteristics. Computational simulations showed that the commissural loads on the leaflet material were significantly reduced by changing the attachment techniques. Hemodynamic analysis showed an effective orifice area of 0.08 cm2, a mean transvalvular pressure gradient of 7.52 mmHg, and a regurgitation fraction of 8.42%, calculated over 100 consecutive cardiac cycles. In conclusion, the FTPVR exhibited good hemodynamic characteristics, and studies with biodegradable stent materials are underway.

Hydrogel-polyurethane fiber composites with enhanced microarchitectural control for heart valve replacement.

Polymeric heart valves offer the potential to overcome the limited durability of tissue based bioprosthetic valves and the need for anticoagulant therapy of mechanical valve replacement options. However, developing a single-phase material with requisite biological properties and target mechanical properties remains a challenge. In this study, a composite heart valve material was developed where an electrospun mesh provides tunable mechanical properties and a hydrogel coating confers an antifouling surface for thromboresistance. Key biological responses were evaluated in comparison to glutaraldehyde-fixed pericardium. Platelet and bacterial attachment were reduced by 38% and 98%, respectively, as compared to pericardium that demonstrated the antifouling nature of the hydrogel coating. There was also a notable reduction (59%) in the calcification of the composite material as compared to pericardium. A custom 3D-printed hydrogel coating setup was developed to make valve composites for device-level hemodynamic testing. Regurgitation fraction (9.6 ± 1.8%) and effective orifice area (1.52 ± 0.34 cm2 ) met ISO 5840-2:2021 requirements. Additionally, the mean pressure gradient was comparable to current clinical bioprosthetic heart valves demonstrating preliminary efficacy. Although the hemodynamic properties are promising, it is anticipated that the random microarchitecture will result in suboptimal strain fields and peak stresses that may accelerate leaflet fatigue and degeneration. Previous computational work has demonstrated that bioinspired fiber microarchitectures can improve strain homogeneity of valve materials toward improving durability. To this end, we developed advanced electrospinning methodologies to achieve polyurethane fiber microarchitectures that mimic or exceed the physiological ranges of alignment, tortuosity, and curvilinearity present in the native valve. Control of fiber alignment from a random fiber orientation at a normalized orientation index (NOI) 14.2 ± 6.9% to highly aligned fibers at a NOI of 85.1 ± 1.4%. was achieved through increasing mandrel rotational velocity. Fiber tortuosity and curvilinearity in the range of native valve features were introduced through a post-spinning annealing process and fiber collection on a conical mandrel geometry, respectively. Overall, these studies demonstrate the potential of hydrogel-polyurethane fiber composite as a heart valve material. Future studies will utilize the developed advanced electrospinning methodologies in combination with model-directed fabrication toward optimizing durability as a function of fiber microarchitecture.

An In-Vitro Study of the Flow Past a Transcatheter Aortic Valve Using Time-Resolved 3D Particle Tracking.

The performance of a transcatheter aortic valve (TAV) can be evaluated by analyzing the flow field downstream of the valve. However, three dimensional flow and pressure fields, and particle residence time, a quantity closely related to thrombosis risk, are challenging to obtain. This experimental study aims to provide a comprehensive 3D measurement of the flow field downstream of an Edwards SAPIEN 3 using time-resolved 3D particle tracking velocimetry (3D PTV) with Shake-the-Box (STB) algorithm. The valve was deployed in an idealized aorta model and tested in a left heart simulator under physiological conditions. Detailed 3D vortical structures, pressure distributions, and particle residence time were obtained by analyzing the 3D particle tracks. Results have shown large-scale retrograde flow entering the sinuses of the TAV at systole, reducing flow stasis there. However, the 3D particle tracks reveal that the retrograde flow has a high residence time and might have already experienced high shear stress near the main jet. Thus by only focusing on the flow in the sinus region is not sufficient to evaluate the leaflet thrombosis risk, and the flow downstream of the valve should be taken into consideration. The unique perspectives offered by 3D PTV are important when evaluating the performance of the TAVs.

Design consideration of a novel polymeric transcatheter heart valve through computational modeling.

Transcatheter heart valve replacement is becoming a more routine procedure, and this is further supported by positive outcomes from studies involving low-risk patients. Nevertheless, the lack of long-term transcatheter heart valve (TAV) durability is still one of the primary concerns. As a result, more research has been focused on improving durability through various methods such as valve design, computational modeling, and material selection. Recent advancements in polymeric valve fabrication showed that linear low-density polyethylene (LLDPE) could be used as leaflet material for transcatheter heart valves. In this paper, a parametric study of computational simulations showed stress distribution on the leaflets of LLDPE-TAV under diastolic load, and the results were used to improve the stent design. The in silico experiment also tested the effect of shock absorbers in terms of valve durability. The results demonstrated that altering specific stent angles can significantly lower peak stress on the leaflets (13.8 vs. 6.07 MPa). Implementing two layers of shock absorbers further reduces the stress value to 4.28 MPa. The pinwheeling index was assessed, which seems to correlate with peak stress. Overall, the parametric study and the computational method can be used to analyze and improve valve durability.

Flow dynamics of surgical and transcatheter aortic valves: Past to present.

Objective: To perform an in vitro characterization of surgical aortic valves (SAVs) and transcatheter aortic valves (TAVs) to highlight the development of the flow dynamics depending on the type of valve implanted and assess the basic differences in the light of flow turbulence and its effect on blood damage likelihood and hemodynamic parameters that shed light on valve performance. Methods: A Starr-Edwards ball and cage valve of internal diameter 22 mm, a 23-mm Medtronic Hancock II SAV, a 23-mm St Jude Trifecta SAV, a 23-mm St Jude SJM (mechanical valve) SAV, a 26-mm Medtronic Evolut TAV, and a 26-mm Edwards SAPIEN 3 TAV were assessed in a pulse duplicator under physiological conditions. Particle image velocimetry was performed for each valve. Pressure gradient and effective orifice area (EOA) along with velocity flow field, Reynolds shear stress (RSS), and viscous shear stress (VSS) were calculated. Results: The SJM mechanical valve exhibited the greatest EOA (1.96 ± 0.02 cm2), showing superiority of efficiency compared with the same-size Trifecta (1.87 ± 0.07 cm2) and Hancock II (1.05 ± 0.01 cm2) (P < .0001). The TAVs show close EOAs (2.10 ± 0.06 cm2 with Evolut and 2.06 ± 0.03 cm2 with SAPIEN 3; P < .0001). The flow characteristics and behavior downstream of the valves differed depending on the valve type, design, and size. The greater the RSS and VSS the more turbulent the downstream flow. Hancock II displays the greatest range of RSS and VSS magnitudes compared with the same-size Trifecta and SJM. The Evolut displays the greatest range of RSS and VSS compared with the SAPIEN 3. Conclusions: The results of this study shed light on numerous advancements in the design of aortic valve replacement prosthesis and the subsequent hemodynamic variations. Future surgical and transcatheter valve designs should aim at not only concentrating on hemodynamic parameters but also at optimizing downstream flow properties.

Gradient and pressure recovery of a self-expandable transcatheter aortic valve depends on ascending aorta size: In vitro study.

Objective: In this study we aimed to understand the role of interaction of the Medtronic Evolut R transcatheter aortic valve with the ascending aorta (AA) by evaluating the performance of the valve and the pressure recovery in different AA diameters with the same aortic annulus size. Methods: A 26-mm Medtronic Evolut R valve was tested using a left heart simulator in aortic root models of different AA diameter (D): small (D = 23 mm), medium (D = 28 mm), and large (D = 34 mm) under physiological conditions. Measurements of pressure from upstream to downstream of the valve were performed using a catheter at small intervals to comprehensively assess pressure gradient and pressure recovery. Results: In the small AA, the measured peak and mean pressure gradient at vena contracta were 11.5 ± 0.5 mm Hg and 7.8 ± 0.4 mm Hg, respectively, which was higher (P < .01) compared with the medium (8.1 ± 0.4 mm Hg and 5.2 ± 0.4 mm Hg) and large AAs (7.4 ± 1.0 mm Hg and 5.4 ± 0.6 mm Hg). The net pressure gradient was lower for the case with the medium AA (4.1 ± 1.2 mm Hg) compared with the small AA (4.7 ± 0.8 mm Hg) and large AA (6.1 ± 1.4 mm Hg; P < .01). Conclusions: We have shown that small and large AAs can increase net pressure gradient, because of the direct interaction of the Medtronic Evolut R stent with the AA (in small AA) and introducing higher level of turbulence (in large AA). AA size might need to be considered in the selection of an appropriate device for transcatheter aortic valve replacement.

Comparison of performance of self-expanding and balloon-expandable transcatheter aortic valves.

Objective: To evaluate the flow dynamics of self-expanding and balloon-expandable transcatheter aortic valves pertaining to turbulence and pressure recovery. Transcatheter aortic valves are characterized by different designs that have different valve performance and outcomes. Methods: Assessment of transcatheter aortic valves was performed using self-expanding devices (26-mm Evolut [Medtronic], 23-mm Allegra [New Valve Technologies], and small Acurate neo [Boston Scientific]) and a balloon-expandable device (23-mm Sapien 3 [Edwards Lifesciences]). Particle image velocimetry assessed the flow downstream. A Millar catheter was used for pressure recovery calculation. Velocity, Reynolds shear stresses, viscous shear stress, and pressure gradients were calculated. Results: The maximal velocity at peak systole obtained with the Evolut R, Sapien 3, Acurate neo, and Allegra was 2.12 ± 0.19 m/sec, 2.41 ± 0.06 m/sec, 2.99 ± 0.10 m/sec, and 2.45 ± 0.08 m/sec, respectively (P < .001). Leaflet oscillations with the flow were clear with the Evolut R and Acurate neo. The Allegra shows the minimal range of Reynolds shear stress magnitudes (up to 320 Pa), and Sapien 3 the maximal (up to 650 Pa). The Evolut had the smallest viscous shear stress magnitude range (up to 3.5 Pa), and the Sapien 3 the largest (up to 6.2 Pa). The largest pressure drop at the vena contracta occurred with the Acurate neo transcatheter aortic valve with a pressure gradient of 13.96 ± 1.35 mm Hg. In the recovery zone, the smallest pressure gradient was obtained with the Allegra (3.32 ± 0.94 mm Hg). Conclusions: Flow dynamics downstream of different transcatheter aortic valves vary significantly depending on the valve type, despite not having a general trend depending on whether or not valves are self-expanding or balloon-expandable. Deployment design did not have an influence on flow dynamics.

Image Registration-Based Method for Reconstructing Transcatheter Heart Valve Geometry from Patient-Specific CT Scans.

Accurate reconstruction of transcatheter aortic valve (TAV) geometries and other stented cardiac devices from computed tomography (CT) images is challenging, mainly associated with blooming artifacts caused by the metallic stents. In addition, bioprosthetic leaflets of TAVs are difficult to segment due to the low signal strengths of the tissues. This paper describes a method that exploits the known device geometry and uses an image registration-based reconstruction method to accurately recover the in vivo stent and leaflet geometries from patient-specific CT images. Error analyses have shown that the geometric error of the stent reconstruction is around 0.1mm, lower than 1/3 of the stent width or most of the CT scan resolutions. Moreover, the method only requires a few human inputs and is robust to input biases. The geometry and the residual stress of the leaflets can be subsequently computed using finite element analysis (FEA) with displacement boundary conditions derived from the registration. Finally, the stress distribution in self-expandable stents can be reasonably estimated by an FEA-based simulation. This method can be used in pre-surgical planning for TAV-in-TAV procedures or for in vivo assessment of surgical outcomes from post-procedural CT scans. It can also be used to reconstruct other medical devices such as coronary stents.

Controlling the Flow Separation in Heart Valves Using Vortex Generators.

A comprehensive computational study is performed to investigate the effectiveness of vortex generators (VGs) applied to mechanical bi-leaflet heart valves. Co-rotating and counter-rotating VG configurations are compared to a control valve without VGs. Detailed flow fields are obtained and used to elucidate the underlying flow physics. It was found that VGs reduce flow separation over the leaflets and hence reduce the Reynolds shear stress (RSS) in the vicinity regions of heart valve. The co-rotating VG configuration demonstrates a better performance compared with the counter-rotating configuration in terms of the RSS, turbulent kinetic energy production and velocity distributions, especially in the peripheral jet flows. The fraction of blood damage in the co-rotating configuration shows a 4.7% reduction in comparison to the control case, while a 3.7% increase is observed in the counter-rotating configuration. The passive flow control technique of applying co-rotating VG illustrates a great potential to help mitigate the hemodynamic factors leading to potential blood damage risk.

Multiple MitraClips: The balancing act between pressure gradient and regurgitation.

OBJECTIVE: Transcatheter mitral valve repair with the MitraClip is used for the symptomatic management of mitral regurgitation (MR). The challenge is reducing MR while avoiding an elevated mitral valve gradient (MVG). This study assesses how multiple MitraClips used to treat MR can affect valve performance. METHODS: Six porcine mitral valves were assessed using an in vitro left heart simulator in the native, moderate-to-severe MR, and severe MR cases. MR cases were tested in the no-MitraClip, 1-MitraClip, and 2-MitraClip configurations. Mitral regurgitant fraction (MRF), MVG, and effective orifice area (EOA) were quantified. RESULTS: Native MRF, MVG, and EOA were 14.22%, 2.59 mm Hg, and 1.64 cm2, respectively. For moderate-to-severe MR, MRF, MVG, and EOA were 34.07%, 3.31 mm Hg, and 2.22 cm2, respectively. Compared with the no-MitraClip case, 1 MitraClip decreased MRF to 18.57% (P < .0001) and EOA to 1.50 cm2 (P = .0002). MVG remained statistically unchanged (3.44 mm Hg). Two MitraClips decreased MRF to 14.26% (P < .0001) and EOA to 1.36 cm2 (P = .0001). MVG remained unchanged (3.29 mm Hg). For severe MR, MRF, MVG, and EOA were 59.79%, 4.98 mm Hg, and 2.73 cm2, respectively. Compared with the no-MitraClip case, 1 MitraClip decreased MRF to 30.72% (P < .0001) and EOA to 1.82 cm2 (P < .0001); MVG remained unchanged (4.03 mm Hg). MVG remained statistically unchanged. Two MitraClips decreased MRF to 23.10% (P < .0001) and EOA to 1.58 cm2 (P < .0001); MVG remained statistically unchanged (3.82 mm Hg). Both MR models yielded no statistical difference between 1 and 2 MitraClips. CONCLUSIONS: There is limited concern regarding elevation of MVG when reducing MR using 1 or 2 MitraClips, although 2 MitraClips did not significantly continue to reduce MRF.

Flow Dynamics in Anomalous Aortic Origin of a Coronary Artery in Children: Importance of the Intramural Segment.

This study aims to assess the differences in pressure, fractional flow reserve (FFR) and coronary flow (with increasing pressure) of the proximal coronary artery in patients with anomalous aortic origin of a coronary artery with a confirmed ischemic event, without ischemic events, and before and after unroofing surgery, and compare to a patient with normal coronary arteries. Patient-specific flow models were 3D printed for 3 subjects with anomalous right coronary arteries with intramural course, 2 of them had documented ischemia, and compared with a patient with normal coronaries. The models were placed in the aortic position of a pulse duplicator and precise measurements to quantify FFR and coronary flow rate were performed from the aortic to the mediastinal segment of the anomalous right coronary artery. In an ischemic model, a gradual FFR drop (emulating that of pressure) was shown from the ostium location (∼1.0) to the distal intramural course (0.48). In nonischemic and normal patient models, FFR for all locations did not drop below 0.9. In a second ischemic model prior to repair, a drop to 0.44 was encountered at the intramural and mediastinal intersection, improving to 0.86 postrepair. There is a difference in instantaneous coronary flow rate with increasing aortic pressure in the ischemic models (slope 0.2846), compared to the postrepair and normal models (slope >0.53). These observations on patient models support a biomechanical basis for ischemia and potentially sudden cardiac death in aortic origin of a coronary artery, with a drop in pressure and FFR in the intramural segment, and a decrease in coronary flow rate with increasing aortic pressure, with both improving after corrective surgery.

Biomechanics of Transcatheter Aortic Valve Replacement Complications and Computational Predictive Modeling.

Transcatheter aortic valve replacement (TAVR) is a rapidly growing field enabling replacement of diseased aortic valves without the need for open heart surgery. However, due to the nature of the procedure and nonremoval of the diseased tissue, there are rates of complications ranging from tissue rupture and coronary obstruction to paravalvular leak, valve thrombosis, and permanent pacemaker implantation. In recent years, computational modeling has shown a great deal of promise in its capabilities to understand the biomechanical implications of TAVR as well as help preoperatively predict risks inherent to device-patient-specific anatomy biomechanical interaction. This includes intricate replication of stent and leaflet designs and tested and validated simulated deployments with structural and fluid mechanical simulations. This review outlines current biomechanical understanding of device-related complications from TAVR and related predictive strategies using computational modeling. An outlook on future modeling strategies highlighting reduced order modeling which could significantly reduce the high time and cost that are required for computational prediction of TAVR outcomes is presented in this review paper. A summary of current commercial/in-development software is presented in the final section.

Predictive Model for Thrombus Formation After Transcatheter Valve Replacement.

PURPOSE: Leaflet thrombosis is a significant adverse event after transcatheter aortic valve (TAV) replacement (TAVR). The purpose of our study was to present a semi-empirical, mathematical model that links patient-specific anatomic, valve, and flow parameters to predict likelihood of leaflet thrombosis. METHODS: The two main energy sources of neo-sinus (NS) washout after TAVR include the jet flow downstream of the TAV and NS geometric change in volume due to the leaflets opening and closing. Both are highly dependent on patient anatomic and hemodynamic factors. As rotation of blood flow is prevalent in both the sinus of Valsalva and then the NS, we adopted the vorticity flux or circulation (Г) as a metric quantifying overall washout. Leaflet thrombus volumes were segmented based on hypo-attenuating leaflet thickening (HALT) in post-TAVR patient's gated computed tomography. Г was assessed using dimensional scaling as well as computational fluid dynamics (CFD) respectively and correlated to the thrombosis volumes using sensitivity and specificity analysis. RESULTS: Г in the NS, that accounted for patient flow and anatomic conditions derived from scaling arguments significantly better predicted the occurrence of leaflet thrombus than CFD derived measures such as stasis volumes or wall shear stress. Given results from the six patient datasets considered herein, a threshold Г value of 28.0 yielded a sensitivity and specificity of 100% where patients with Gamma < 28 developed valve thrombosis. A 10% error in measurements of all variables can bring the sensitivity specificity down to 87%. CONCLUSION: A predictive model relating likelihood of valve thrombosis using Г in the NS was developed with promising sensitivity and specificity. With further studies and improvements, this predictive technology may lead to alerting physicians on the risk for thrombus formation following TAVR.