High Shear Stress Reduces ERG Causing Endothelial-Mesenchymal Transition and Pulmonary Arterial Hypertension.

Pathological high shear stress (HSS, 100 dyn/cm 2 ) is generated in distal pulmonary arteries (PA) (100-500 µm) in congenital heart defects and in progressive PA hypertension (PAH) with inward remodeling and luminal narrowing. Human PA endothelial cells (PAEC) were subjected to HSS versus physiologic laminar shear stress (LSS, 15 dyn/cm 2 ). Endothelial-mesenchymal transition (EndMT), a feature of PAH not previously attributed to HSS, was observed. H3K27ac peaks containing motifs for an ETS-family transcription factor (ERG) were reduced, as was ERG-Krüppel-like factors (KLF)2/4 interaction and ERG expression. Reducing ERG by siRNA in PAEC during LSS caused EndMT; transfection of ERG in PAEC under HSS prevented EndMT. An aorto-caval shunt was preformed in mice to induce HSS and progressive PAH. Elevated PA pressure, EndMT and vascular remodeling were reduced by an adeno-associated vector that selectively replenished ERG in PAEC. Agents maintaining ERG in PAEC should overcome the adverse effect of HSS on progressive PAH.

4D flow cardiovascular magnetic resonance recovery profiles following pulmonary endarterectomy in chronic thromboembolic pulmonary hypertension.

BACKGROUND: Four-dimensional flow cardiovascular magnetic resonance imaging (4D flow CMR) allows comprehensive assessment of pulmonary artery (PA) flow dynamics. Few studies have characterized longitudinal changes in pulmonary flow dynamics and right ventricular (RV) recovery following a pulmonary endarterectomy (PEA) for patients with chronic thromboembolic pulmonary hypertension (CTEPH). This can provide novel insights of RV and PA dynamics during recovery. We investigated the longitudinal trajectory of 4D flow metrics following a PEA including velocity, vorticity, helicity, and PA vessel wall stiffness. METHODS: Twenty patients with CTEPH underwent pre-PEA and > 6 months post-PEA CMR imaging including 4D flow CMR; right heart catheter measurements were performed in 18 of these patients. We developed a semi-automated pipeline to extract integrated 4D flow-derived main, left, and right PA (MPA, LPA, RPA) volumes, velocity flow profiles, and secondary flow profiles. We focused on secondary flow metrics of vorticity, volume fraction of positive helicity (clockwise rotation), and the helical flow index (HFI) that measures helicity intensity. RESULTS: Mean PA pressures (mPAP), total pulmonary resistance (TPR), and normalized RV end-systolic volume (RVESV) decreased significantly post-PEA (P < 0.002). 4D flow-derived PA volumes decreased (P < 0.001) and stiffness, velocity, and vorticity increased (P < 0.01) post-PEA. Longitudinal improvements from pre- to post-PEA in mPAP were associated with longitudinal decreases in MPA area (r = 0.68, P = 0.002). Longitudinal improvements in TPR were associated with longitudinal increases in the maximum RPA HFI (r=-0.85, P < 0.001). Longitudinal improvements in RVESV were associated with longitudinal decreases in MPA fraction of positive helicity (r = 0.75, P = 0.003) and minimum MPA HFI (r=-0.72, P = 0.005). CONCLUSION: We developed a semi-automated pipeline for analyzing 4D flow metrics of vessel stiffness and flow profiles. PEA was associated with changes in 4D flow metrics of PA flow profiles and vessel stiffness. Longitudinal analysis revealed that PA helicity was associated with pulmonary remodeling and RV reverse remodeling following a PEA.

Blood flow modeling reveals improved collateral artery performance during the regenerative period in mammalian hearts.

Collateral arteries bridge opposing artery branches, forming a natural bypass that can deliver blood flow downstream of an occlusion. Inducing coronary collateral arteries could treat cardiac ischemia, but more knowledge on their developmental mechanisms and functional capabilities is required. Here we used whole-organ imaging and three-dimensional computational fluid dynamics modeling to define spatial architecture and predict blood flow through collaterals in neonate and adult mouse hearts. Neonate collaterals were more numerous, larger in diameter and more effective at restoring blood flow. Decreased blood flow restoration in adults arose because during postnatal growth coronary arteries expanded by adding branches rather than increasing diameters, altering pressure distributions. In humans, adult hearts with total coronary occlusions averaged 2 large collaterals, with predicted moderate function, while normal fetal hearts showed over 40 collaterals, likely too small to be functionally relevant. Thus, we quantify the functional impact of collateral arteries during heart regeneration and repair-a critical step toward realizing their therapeutic potential.

Computational simulation-derived hemodynamic and biomechanical properties of the pulmonary arterial tree early in the course of ventricular septal defects.

Untreated ventricular septal defects (VSDs) can lead to pulmonary arterial hypertension (PAH) characterized by elevated pulmonary artery (PA) pressure and vascular remodeling, known as PAH associated with congenital heart disease (PAH-CHD). Though previous studies have investigated hemodynamic effects on vascular mechanobiology in late-stage PAH, hemodynamics leading to PAH-CHD initiation have not been fully quantified. We hypothesize that abnormal hemodynamics from left-to-right shunting in early stage VSDs affects PA biomechanical properties leading to PAH initiation. To model PA hemodynamics in healthy, small, moderate, and large VSD conditions prior to the onset of vascular remodeling, computational fluid dynamics simulations were performed using a 3D finite element model of a healthy 1-year-old's proximal PAs and a body-surface-area-scaled 0D distal PA tree. VSD conditions were modeled with increased pulmonary blood flow to represent degrees of left-to-right shunting. In the proximal PAs, pressure, flow, strain, and wall shear stress (WSS) increased with increasing VSD size; oscillatory shear index decreased with increasing VSD size in the larger PA vessels. WSS was higher in smaller diameter vessels and increased with VSD size, with the large VSD condition exhibiting WSS >100 dyn/cm[Formula: see text], well above values typically used to study dysfunctional mechanotransduction pathways in PAH. This study is the first to estimate hemodynamic and biomechanical metrics in the entire pediatric PA tree with VSD severity at the stage leading to PAH initiation and has implications for future studies assessing effects of abnormal mechanical stimuli on endothelial cells and vascular wall mechanics that occur during PAH-CHD initiation and progression.

The nested block preconditioning technique for the incompressible Navier-Stokes equations with emphasis on hemodynamic simulations.

We develop a novel iterative solution method for the incompressible Navier-Stokes equations with boundary conditions coupled with reduced models. The iterative algorithm is designed based on the variational multiscale formulation and the generalized-α scheme. The spatiotemporal discretization leads to a block structure of the resulting consistent tangent matrix in the Newton-Raphson procedure. As a generalization of the conventional block preconditioners, a three-level nested block preconditioner is introduced to attain a better representation of the Schur complement, which plays a key role in the overall algorithm robustness and efficiency. This approach provides a flexible, algorithmic way to handle the Schur complement for problems involving multiscale and multiphysics coupling. The solution method is implemented and benchmarked against experimental data from the nozzle challenge problem issued by the US Food and Drug Administration. The robustness, efficiency, and parallel scalability of the proposed technique are then examined in several settings, including moderately high Reynolds number flows and physiological flows with strong resistance effect due to coupled downstream vasculature models. Two patient-specific hemodynamic simulations, covering systemic and pulmonary flows, are performed to further corroborate the efficacy of the proposed methodology.

Image-based scaling laws for somatic growth and pulmonary artery morphometry from infancy to adulthood.

Pulmonary artery (PA) morphometry has been extensively explored in adults, with particular focus on intra-acinar arteries. However, scaling law relationships for length and diameter of extensive preacinar PAs by age have not been previously reported for in vivo human data. To understand preacinar PA growth spanning children to adults, we performed morphometric analyses of all PAs visible in the computed tomography (CT) and magnetic resonance (MR) images from a healthy subject cohort [n = 16; age: 1-51 yr; body surface area (BSA): 0.49-2.01 m2]. Subject-specific anatomic PA models were constructed from CT and MR images, and morphometric information-diameter, length, tortuosity, bifurcation angle, and connectivity-was extracted and sorted into diameter-defined Strahler orders. Validation of Murray's law, describing optimal scaling exponents of radii for branching vessels, was performed to determine how closely PAs conform to this classical relationship. Using regression analyses of vessel diameters and lengths against orders and patient metrics (BSA, age, height), we found that diameters increased exponentially with order and allometrically with patient metrics. Length increased allometrically with patient metrics, albeit weakly. The average tortuosity index of all vessels was 0.026 ± 0.024, average bifurcation angle was 28.2 ± 15.1°, and average Murray's law exponent was 2.92 ± 1.07. We report a set of scaling laws for vessel diameter and length, along with other morphometric information. These provide an initial understanding of healthy structural preacinar PA development with age, which can be used for computational modeling studies and comparison with diseased PA anatomy.NEW & NOTEWORTHY Pulmonary artery (PA) morphometry studies to date have focused primarily on large arteries and intra-acinar arteries in either adults or children, neglecting preacinar arteries in both populations. Our study is the first to quantify in vivo preacinar PA morphometry changes spanning infants to adults. For preacinar arteries > 1 mm in diameter, we identify scaling laws for vessel diameters and lengths with patient metrics of growth and establish a healthy PA morphometry baseline for most preacinar PAs.

Integrated Image-Based Computational Fluid Dynamics Modeling Software as an Instructional Tool.

Computational modeling of cardiovascular flows is becoming increasingly important in a range of biomedical applications, and understanding the fundamentals of computational modeling is important for engineering students. In addition to their purpose as research tools, integrated image-based computational fluid dynamics (CFD) platforms can be used to teach the fundamental principles involved in computational modeling and generate interest in studying cardiovascular disease. We report the results of a study performed at five institutions designed to investigate the effectiveness of an integrated modeling platform as an instructional tool and describe "best practices" for using an integrated modeling platform in the classroom. Use of an integrated modeling platform as an instructional tool in nontraditional educational settings (workshops, study abroad programs, in outreach) is also discussed. Results of the study show statistically significant improvements in understanding after using the integrated modeling platform, suggesting such platforms can be effective tools for teaching fundamental cardiovascular computational modeling principles.

Evolution of hemodynamic forces in the pulmonary tree with progressively worsening pulmonary arterial hypertension in pediatric patients.

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling resulting in right ventricular (RV) dysfunction and ultimately RV failure. Mechanical stimuli acting on the vessel walls of the full pulmonary tree have not previously been comprehensively characterized. The goal of this study is to characterize wall shear stress (WSS) and strain in pediatric PAH patients at different stages of disease severity using computational patient-specific modeling. Computed tomography, magnetic resonance imaging and right heart catheterization data were collected and assimilated into pulmonary artery (PA) models for patients with and without PAH. Patients were grouped in three disease severity groups (control, moderate and severe) based on clinical evaluations. A finite element solver was employed to quantify hemodynamics and wall strains. To estimate WSS in the distal small PAs with diameters ranging from 50 to 500 [Formula: see text], a morphometric tree model was created, with inputs coming from outlets of the 3D model. WSS in the proximal PAs decreased with disease severity (control 20.5 vs. moderate 15.8 vs. severe 6.3 [Formula: see text], [Formula: see text]). Oscillatory shear index increased in the main pulmonary artery (MPA) with disease severity (0.13 vs. 0.13 vs. 0.2, [Formula: see text]). Wall strains measured by the first invariant of Green strain tensor decreased with disease severity (0.16 vs. 0.12 vs. 0.11, [Formula: see text]). Mean WSS for the distal PAs between 100 and 500 [Formula: see text] significantly increased with disease severity (20 vs. 52 vs. 116 [Formula: see text], [Formula: see text]). In conclusion, 3D flow simulations showed that WSS is significantly decreased in the MPA with disease while the mathematical morphometric model suggested increased WSS in the distal small vessels. Computational models can reveal mechanical stimuli acting on vessel walls that may inform patient risk stratification and flow shear experiments.

Magnitude, decadal changes, and impact of regional background ozone transported into the greater Houston, Texas, area.

Two independent analyses of the daily maximum 8 h average ozone concentrations measured during the high ozone season (May through October) at Continuous Ambient Monitoring Stations are used to quantify the regional background ozone transported into the Houston-Galveston-Brazoria (HGB) area. The dependence on wind direction is examined, and long-term trends are determined using measurements made between 1998 and 2012. Both analyses show that the regional background ozone has declined during periods of continental outflow: i.e., the conditions associated with most high ozone episodes in HGB. The changes in regional background ozone found for northeasterly and southeasterly flow are -0.50 ± 0.54 and -0.79 ± 0.65 (95% confidence limit) ppbv yr(-1), respectively, which correspond to decreases of ∼7-11 ppbv between 1998 and 2012. This finding is consistent with the summertime downward trend of -0.45 ppbv yr(-1) (range of sites: -0.87 to +0.07 ppbv yr(-1)) for ozone in the eastern U.S. between 1990 and 2010 reported by Cooper et al. and shows that changing background concentrations are at least partially responsible for the decreased surface ozone in the HGB area over the past decade. Baseline ozone concentrations in air flowing into Texas from the Gulf of Mexico have not changed significantly over this period.