Showing papers by "Juan C. del Álamo published in 2021"

Demonstration of Patient-Specific Simulations to Assess Left Atrial Appendage Thrombogenesis Risk.

Abstract: Atrial fibrillation (AF) alters left atrial (LA) hemodynamics, which can lead to thrombosis in the left atrial appendage (LAA), systemic embolism and stroke. A personalized risk-stratification of AF patients for stroke would permit improved balancing of preventive anticoagulation therapies against bleeding risk. We investigated how LA anatomy and function impact LA and LAA hemodynamics, and explored whether patient-specific analysis by computational fluid dynamics (CFD) can predict the risk of LAA thrombosis. We analyzed 4D-CT acquisitions of LA wall motion with an in-house immersed-boundary CFD solver. We considered six patients with diverse atrial function, three with either a LAA thrombus (removed digitally before running the simulations) or a history of transient ischemic attacks (LAAT/TIA-pos), and three without a LAA thrombus or TIA (LAAT/TIA-neg). We found that blood inside the left atrial appendage of LAAT/TIA-pos patients had marked alterations in residence time and kinetic energy when compared with LAAT/TIA-neg patients. In addition, we showed how the LA conduit, reservoir and booster functions distinctly affect LA and LAA hemodynamics. Finally, fixed-wall and moving-wall simulations produced different LA hemodynamics and residence time predictions for each patient. Consequently, fixed-wall simulations risk-stratified our small cohort for LAA thrombosis worse than moving-wall simulations, particularly patients with intermediate LAA residence time. Overall, these results suggest that both wall kinetics and LAA morphology contribute to LAA blood stasis and thrombosis.

Fibrosis, atrial fibrillation and stroke: clinical updates and emerging mechanistic models

Abstract: The current paradigm of stroke risk assessment and mitigation in patients with atrial fibrillation (AF) is centred around clinical risk factors which, in the presence of AF, lead to thrombus formation. The mechanisms by which these clinical risk factors lead to thromboembolism, including any role played by atrial fibrosis, are not understood. In patients who had embolic stroke of undetermined source (ESUS), the problem is compounded by the absence of AF in a majority of patients despite long-term monitoring. Atrial fibrosis has emerged as a unifying mechanism that independently provides a substrate for arrhythmia and thrombus formation. Fibrosis-based computational models of AF initiation and maintenance promise to identify therapeutic targets in catheter ablation. In ESUS, fibrosis is also increasingly recognised as a major risk factor, but the underlying mechanism of this correlation is unclear. Simulations have uncovered potential vulnerability to arrhythmia induction in patients who had ESUS. Likewise, computational models of fluid dynamics representing blood flow in the left atrium and left atrium appendage have improved our understanding of thrombus formation, in particular left atrium appendage shapes and blood flow changes influenced by atrial remodelling. Multiscale modelling of blood flow dynamics based on structural fibrotic and morphological changes with associated cellular and tissue electrical remodelling leading to electromechanical abnormalities holds tremendous promise in providing a mechanistic understanding of the clinical problem of thromboembolisation. We present a review of clinical knowledge alongside computational modelling frameworks and conclude with a vision of a future paradigm integrating simulations in formulating personalised treatment plans for each patient.

Intraventricular Flow Patterns in Patients Treated with Left Ventricular Assist Devices.

Abstract: The success of left ventricular assist device (LVAD) therapy is hampered by complications such as thrombosis and bleeding. Understanding blood flow interactions between the heart and the LVAD might help optimize treatment and decrease complication rates. We hypothesized that LVADs modify shear stresses and blood transit in the left ventricle (LV) by changing flow patterns and that these changes can be characterized using 2D echo color Doppler velocimetry (echo-CDV). We used echo-CDV and custom postprocessing methods to map blood flow inside the LV in patients with ongoing LVAD support (Heartmate II, N = 7). We compared it to healthy controls (N = 20) and patients with dilated cardiomyopathy (DCM, N = 20). We also analyzed intraventricular flow changes during LVAD ramp tests (baseline ± 400 rpm). LVAD support reversed the increase in blood stasis associated with DCM, but it did not reduce intraventricular shear exposure. Within the narrow range studied, the ventricular flow was mostly insensitive to changes in pump speed. Patients with significant aortic insufficiency showed abnormalities in blood stasis and shear indices. Overall, this study suggests that noninvasive flow imaging could potentially be used in combination with standard clinical methods for adjusting LVAD settings to optimize flow transport and minimize stasis on an individual basis.

The interplay between matrix deformation and the coordination of turning events governs directed neutrophil migration in 3D matrices.

Abstract: Neutrophils migrating through extravascular spaces must negotiate narrow matrix pores without losing directional movement. We investigated how chemotaxing neutrophils probe matrices and adjust their migration to collagen concentration ([col]) changes by tracking 20,000 cell trajectories and quantifying cell-generated 3D matrix deformations. In low-[col] matrices, neutrophils exerted large deformations and followed straight trajectories. As [col] increased, matrix deformations decreased, and neutrophils turned often to circumvent rather than remodel matrix pores. Inhibiting protrusive or contractile forces shifted this transition to lower [col], implying that mechanics play a crucial role in defining migratory strategies. To balance frequent turning and directional bias, neutrophils used matrix obstacles as pivoting points to steer toward the chemoattractant. The Actin Related Protein 2/3 complex coordinated successive turns, thus controlling deviations from chemotactic paths. These results offer an improved understanding of the mechanisms and molecular regulators used by neutrophils during chemotaxis in restrictive 3D environments.

Elucidating the Biomechanics of Leukocyte Transendothelial Migration by Quantitative Imaging.

Abstract: Leukocyte transendothelial migration is crucial for innate immunity and inflammation. Upon tissue damage or infection, leukocytes exit blood vessels by adhering to and probing vascular endothelial cells (VECs), breaching endothelial cell-cell junctions, and transmigrating across the endothelium. Transendothelial migration is a critical rate-limiting step in this process. Thus, leukocytes must quickly identify the most efficient route through VEC monolayers to facilitate a prompt innate immune response. Biomechanics play a decisive role in transendothelial migration, which involves intimate physical contact and force transmission between the leukocytes and the VECs. While quantifying these forces is still challenging, recent advances in imaging, microfabrication, and computation now make it possible to study how cellular forces regulate VEC monolayer integrity, enable efficient pathfinding, and drive leukocyte transmigration. Here we review these recent advances, paying particular attention to leukocyte adhesion to the VEC monolayer, leukocyte probing of endothelial barrier gaps, and transmigration itself. To offer a practical perspective, we will discuss the current views on how biomechanics govern these processes and the force microscopy technologies that have enabled their quantitative analysis, thus contributing to an improved understanding of leukocyte migration in inflammatory diseases.

Unraveling the embryonic fate map through the mechanical signature of cells and their trajectories

Abstract: Digital cell lineages reconstructed from 3D+time imaging data of the developing zebrafish embryo are used to uncover mechanical cues and their role in morphogenesis. A continuous approximation of cell displacements obtained from cell lineages is used to assess tissue deformation during gastrulation. At this stage, embryonic tissues display multi-scale compressible fluid-like properties. The deformation rate at the mesoscopic level of the cell’s immediate surroundings appears noisy, in both space and time. The patterns identified by clustering the cells, according to the cumulative deformation rate along their trajectory throughout gastrulation, lead to a robust, ordered and coherent biomechanical map. The timing and amplitude of the biomechanical deformations provide a measurement of the phenotypic variability in small cohorts of specimens. We show that the biomechanical map matches the embryonic fate map of the zebrafish presumptive forebrain, in both wild type and Nodal pathway mutants (zoeptz57/tz57), where it reveals the biomechanical defects that lead to cyclopia.. The comparison of biomechanical patterns and the expression pattern of a transgenic reporter for the transcription factor goosecoid (gsc), supports the hypothesis that embryonic cells acquire, at an early developmental stage, a biomechanical signature that contributes to defining their fate.

Biomechanical interactions of Schistosoma mansoni eggs with vascular endothelial cells facilitate egg extravasation

Abstract: The eggs of the parasitic blood fluke, Schistosoma, are the main drivers of the chronic pathologies associated with schistosomiasis, a disease of poverty afflicting approximately 220 million people worldwide. Eggs laid by Schistosoma mansoni in the bloodstream of the host are encapsulated by vascular endothelial cells (VECs), the first step in the migration of the egg from the blood stream into the lumen of the gut and eventual exit from the body. The biomechanics associated with encapsulation and extravasation of the egg are poorly understood. We demonstrate that S. mansoni eggs induce VECs to form two types of membrane extensions during encapsulation; filopodia that probe eggshell surfaces and intercellular nanotubes that presumably facilitate VEC communication. Encapsulation efficiency, the number of filopodia and intercellular nanotubes, and the length of these structures depend on the eggs vitality and, to a lesser degree, its maturation state. During encapsulation, live eggs induce VEC contractility and membranous structures formation, in a Rho/ROCK pathway-dependent manner. Using elastic hydrogels embedded with fluorescent microbeads as substrates to culture VECs, live eggs induce VECs to exert significantly greater contractile forces during encapsulation than dead eggs, which leads to 3D deformations on both the VEC monolayer and the flexible substrate underneath. These significant mechanical deformations cause the VEC monolayer tension to fluctuate with eventual rupture of VEC junctions, thus facilitating egg transit out of the blood vessel. Overall, our data on the mechanical interplay between host VECs and the schistosome egg improve our understanding of how this parasite manipulates its immediate environment to maintain disease transmission.