Venous Thromboembolism: Review of Clinical Challenges, Biology, Assessment, Treatment, and Modeling.

Venous thromboembolism (VTE) is a massive clinical challenge, annually affecting millions of patients globally. VTE is a particularly consequential pathology, as incidence is correlated with extremely common risk factors, and a large cohort of patients experience recurrent VTE after initial intervention. Altered hemodynamics, hypercoagulability, and damaged vascular tissue cause deep-vein thrombosis and pulmonary embolism, the two permutations of VTE. Venous valves have been identified as likely locations for initial blood clot formation, but the exact pathway by which thrombosis occurs in this environment is not entirely clear. Several risk factors are known to increase the likelihood of VTE, particularly those that increase inflammation and coagulability, increase venous resistance, and damage the endothelial lining. While these risk factors are useful as predictive tools, VTE diagnosis prior to presentation of outward symptoms is difficult, chiefly due to challenges in successfully imaging deep-vein thrombi. Clinically, VTE can be managed by anticoagulants or mechanical intervention. Recently, direct oral anticoagulants and catheter-directed thrombolysis have emerged as leading tools in resolution of venous thrombosis. While a satisfactory VTE model has yet to be developed, recent strides have been made in advancing in silico models of venous hemodynamics, hemorheology, fluid-structure interaction, and clot growth. These models are often guided by imaging-informed boundary conditions or inspired by benchtop animal models. These gaps in knowledge are critical targets to address necessary improvements in prediction and diagnosis, clinical management, and VTE experimental and computational models.

4D Flow Patterns and Relative Pressure Distribution in a Left Ventricle Model by Shake-the-Box and Proper Orthogonal Decomposition Analysis.

PURPOSE: Intraventricular blood flow dynamics are associated with cardiac function. Accurate, noninvasive, and easy assessments of hemodynamic quantities (such as velocity, vortex, and pressure) could be an important addition to the clinical diagnosis and treatment of heart diseases. However, the complex time-varying flow brings many challenges to the existing noninvasive image-based hemodynamic assessments. The development of reliable techniques and analysis tools is essential for the application of hemodynamic biomarkers in clinical practice. METHODS: In this study, a time-resolved particle tracking method, Shake-the-Box, was applied to reconstruct the flow in a realistic left ventricle (LV) silicone model with biological valves. Based on the obtained velocity, 4D pressure field was calculated using a Poisson equation-based pressure solver. Furthermore, flow analysis by proper orthogonal decomposition (POD) of the 4D velocity field has been performed. RESULTS: As a result of the Shake-the-Box algorithm, we have extracted: (i) particle positions, (ii) particle tracks, and finally, (iii) 4D velocity fields. From the latter, the temporal evolution of the 3D pressure field during the full cardiac cycle was obtained. The obtained maximal pressure difference extracted along the base-to-apex was about 2.7 mmHg, which is in good agreement with those reported in vivo. The POD analysis results showed a clear picture of different scale of vortices in the pulsatile LV flow, together with their time-varying information and corresponding kinetic energy content. To reconstruct 95% of the kinetic energy of the LV flow, only the first six POD modes would be required, leading to significant data reduction. CONCLUSIONS: This work demonstrated Shake-the-Box is a promising technique to accurately reconstruct the left ventricle flow field in vitro. The good spatial and temporal resolutions of the velocity measurements enabled a 4D reconstruction of the pressure field in the left ventricle. The application of POD analysis showed its potential in reducing the complexity of the high-resolution left ventricle flow measurements. For future work, image analysis, multi-modality flow assessments, and the development of new flow-derived biomarkers can benefit from fast and data-reducing POD analysis.

Performance of a Hydrogel Coated Nitinol with Oligonucleotide-Modified Nanoparticles Within Turbulent Conditions of Blood-Contacting Devices.

INTRODUCTION: Hydrogels offer a wide range of applications in the antithrombotic modification of biomedical devices. The functionalization of these hydrogels with potentially drug-laden nanoparticles in the context of deviceassociated turbulence is critically under-studied. Thus, the purpose of this study was to use a hydrogel-coating nitinol surface as a model to understand the functions of hydrogels and the capture of nanoparticles under clinically relevant flow conditions. METHODS: Nitinol was coated by an oligonucleotide (ON) functionalized hydrogel. Nanoparticles were functionalized with complementary oligonucleotides (CONs). The capture of CONfunctionalized nanoparticles by the ON-functionalized hydrogel surfaces was studied under both static and dynamic attachment conditions. Fluorescent-labelling of nanoparticles was utilized to assess capture efficacy and resistance to removal by device-relevant flow conditions. RESULTS: The specificity of the ON-CON bond was verified, exhibiting a dose-dependent attachment response. The hydrogel coating was resistant to stripping by flow, retaining >95% after exposure to one hour of turbulent flow. Attachment of nanoparticles to the hydrogel was higher in the static condition than under laminar flow (p < 0.01), but comparable to that of attachment under turbulent flow. Modified nitinol samples underwent one hour of flow treatment under both laminar and turbulent regimes and demonstrated decreased nanoparticle loss following static conjugation rather than turbulent conjugation (36.1% vs 53.8%, p < 0.05). There was no significant difference in nanoparticle functionalization by upstream injection between laminar and turbulent flow. CONCLUSION: The results demonstrate promising potential of hydrogelfunctionalized nitinol for capturing nanoparticles using nucleic acid hybridization. The hydrogel structure and ONCON bond integrity both demonstrated a resistance to mechanical damage and loss of biomolecular functionalization by exposure to turbulence. Further investigation is warranted to highlight drug delivery and antithrombogenic modification applications of nanoparticle-functionalized hydrogels.

Echo planar imaging-induced errors in intracardiac 4D flow MRI quantification.

PURPOSE: To assess errors associated with EPI-accelerated intracardiac 4D flow MRI (4DEPI) with EPI factor 5, compared with non-EPI gradient echo (4DGRE). METHODS: Three 3T MRI experiments were performed comparing 4DEPI to 4DGRE: steady flow through straight tubes, pulsatile flow in a left-ventricle phantom, and intracardiac flow in 10 healthy volunteers. For each experiment, 4DEPI was repeated with readout and blip phase-encoding gradient in different orientations, parallel or perpendicular to the flow direction. In vitro flow rates were compared with timed volumetric collection. In the left-ventricle phantom and in vivo, voxel-based speed and spatio-temporal median speed were compared between sequences, as well as mitral and aortic transvalvular net forward volume. RESULTS: In steady-flow phantoms, the flow rate error was largest (12%) for high velocity (>2 m/s) with 4DEPI readout gradient parallel to the flow. Voxel-based speed and median speed in the left-ventricle phantom were ≤5.5% different between sequences. In vivo, mean net forward volume inconsistency was largest (6.4 ± 8.5%) for 4DEPI with nonblip phase-encoding gradient parallel to the main flow. The difference in median speed for 4DEPI versus 4DGRE was largest (9%) when the 4DEPI readout gradient was parallel to the flow. CONCLUSIONS: Velocity and flow rate are inaccurate for 4DEPI with EPI factor 5 when flow is parallel to the readout or blip phase-encoding gradient. However, mean differences in flow rate, voxel-based speed, and spatio-temporal median speed were acceptable (≤10%) when comparing 4DEPI to 4DGRE for intracardiac flow in healthy volunteers.

4-D Echo-Particle Image Velocimetry in a Left Ventricular Phantom.

Left ventricular (LV) blood flow is an inherently complex time-varying 3-D phenomenon, where 2-D quantification often ignores the effect of out-of-plane motion. In this study, we describe high frame rate 4-D echocardiographic particle image velocimetry (echo-PIV) using a prototype matrix transesophageal transducer and a dynamic LV phantom for testing the accuracy of echo-PIV in the presence of complex flow patterns. Optical time-resolved tomographic PIV (tomo-PIV) was used as a reference standard for comparison. Echo-PIV and tomo-PIV agreed on the general profile of the LV flow patterns, but echo-PIV smoothed out the smaller flow structures. Echo-PIV also underestimated the flow rates at greater imaging depths, where the PIV kernel size and transducer point spread function were large relative to the velocity gradients. We demonstrate that 4-D echo-PIV could be performed in just four heart cycles, which would require only a short breath-hold, providing promising results. However, methods for resolving high velocity gradients in regions of poor spatial resolution are required before clinical translation.

Tomographic PIV in a model of the left ventricle: 3D flow past biological and mechanical heart valves.

Left ventricular flow is intrinsically complex, three-dimensional and unsteady. Its features are susceptible to cardiovascular pathology and treatment, in particular to surgical interventions involving the valves (mitral valve replacement). To improve our understanding of intraventricular fluid mechanics and the impact of various types of prosthetic valves thereon, we have developed a custom-designed versatile left ventricular phantom with anatomically realistic moving left ventricular membrane. A biological, a tilting disc and a bileaflet valve (in two different orientations) were mounted in the mitral position and tested under the same settings. To investigate 3D flow within the phantom, a four-view tomographic particle image velocimetry setup has been implemented. The results compare side-by-side the evolution of the 3D flow topology, vortical structures and kinetic energy in the left ventricle domain during the cardiac cycle. Except for the tilting disc valve, all tested prosthetic valves induced a crossed flow path, where the outflow crosses the inflow path, passing under the mitral valve. The biological valve shows a strong jet with a peak velocity about twice as high compared to all mechanical heart valves, which makes it easier to penetrate deeply into the cavity. Accordingly, the peak kinetic energy in the left ventricle in case of the biological valve is about four times higher than the mechanical heart valves. We conclude that the tomographic particle imaging velocimetry setup provides a useful ground truth measurement of flow features and allows a comparison of the effects of different valve types on left ventricular flow patterns.