3D Imaging Reveals Complex Microvascular Remodeling in the Right Ventricle in Pulmonary Hypertension.

BACKGROUND: Pathogenic concepts of right ventricular (RV) failure in pulmonary arterial hypertension focus on a critical loss of microvasculature. However, the methods underpinning prior studies did not take into account the 3-dimensional (3D) aspects of cardiac tissue, making accurate quantification difficult. We applied deep-tissue imaging to the pressure-overloaded RV to uncover the 3D properties of the microvascular network and determine whether deficient microvascular adaptation contributes to RV failure. METHODS: Heart sections measuring 250-µm-thick were obtained from mice after pulmonary artery banding (PAB) or debanding PAB surgery and properties of the RV microvascular network were assessed using 3D imaging and quantification. Human heart tissues harvested at the time of transplantation from pulmonary arterial hypertension cases were compared with tissues from control cases with normal RV function. RESULTS: Longitudinal 3D assessment of PAB mouse hearts uncovered complex microvascular remodeling characterized by tortuous, shorter, thicker, highly branched vessels, and overall preserved microvascular density. This remodeling process was reversible in debanding PAB mice in which the RV function recovers over time. The remodeled microvasculature tightly wrapped around the hypertrophied cardiomyocytes to maintain a stable contact surface to cardiomyocytes as an adaptation to RV pressure overload, even in end-stage RV failure. However, microvasculature-cardiomyocyte contact was impaired in areas with interstitial fibrosis where cardiomyocytes displayed signs of hypoxia. Similar to PAB animals, microvascular density in the RV was preserved in patients with end-stage pulmonary arterial hypertension, and microvascular architectural changes appeared to vary by etiology, with patients with pulmonary veno-occlusive disease displaying a lack of microvascular complexity with uniformly short segments. CONCLUSIONS: 3D deep tissue imaging of the failing RV in PAB mice, pulmonary hypertension rats, and patients with pulmonary arterial hypertension reveals complex microvascular changes to preserve the microvascular density and maintain a stable microvascular-cardiomyocyte contact. Our studies provide a novel framework to understand microvascular adaptation in the pressure-overloaded RV that focuses on cell-cell interaction and goes beyond the concept of capillary rarefaction.

Digital Spatial Profiling Identifies Distinct Molecular Signatures of Vascular Lesions in Pulmonary Arterial Hypertension.

RATIONALE: Idiopathic Pulmonary Arterial Hypertension (IPAH) is characterized by extensive pulmonary vascular remodeling due to plexiform and obliterative lesions, media hypertrophy, inflammatory cell infiltration, and alterations of the adventitia. OBJECTIVE: Test the hypothesis that microscopic IPAH vascular lesions express unique molecular profiles, which collectively are different from control pulmonary arteries. METHODS: We used digital spatial transcriptomics to profile the genome-wide differential transcriptomic signature of key pathological lesions (plexiform, obliterative, intima+media hypertrophy, and adventitia) in IPAH lungs (n= 11) and compared these data to the intima+media and adventitia of control pulmonary artery (n=5). RESULTS: We detected 8273 transcripts in the IPAH lesions and control lung pulmonary arteries. Plexiform lesions and IPAH adventitia exhibited the greatest number of differentially expressed genes when compared with intima-media hypertrophy and obliterative lesions. Plexiform lesions in IPAH showed enrichment for (i) genes associated with TGFß-signaling and (ii) mutated genes affecting the extracellular matrix and endothelial-mesenchymal transformation. Plexiform lesions and IPAH adventitia showed upregulation of genes involved in immune and interferon signaling, coagulation, and complement pathways. Cellular deconvolution indicated variability in the number of vascular and inflammatory cells between IPAH lesions, which underlies the differential transcript profiling. CONCLUSIONS: IPAH lesions express unique molecular transcript profiles enriched for pathways involving pathogenetic pathways, including genetic disease drivers, innate and acquired immunity, hypoxia sensing, and angiogenesis signaling. These data provide a rich molecular-structural framework in IPAH vascular lesions that inform novel biomarkers and therapeutic targets in this highly morbid disease.

Mapping sleep's oscillatory events as a biomarker of Alzheimer's disease.

INTRODUCTION: Memory-associated neural circuits produce oscillatory events including theta bursts (TBs), sleep spindles (SPs), and slow waves (SWs) in sleep electroencephalography (EEG). Changes in the "coupling" of these events may indicate early Alzheimer's disease (AD) pathogenesis. METHODS: We analyzed 205 aging adults using single-channel sleep EEG, cerebrospinal fluid (CSF) AD biomarkers, and Clinical Dementia Rating® (CDR®) scale. We mapped SW-TB and SW-SP neural circuit coupling precision to amyloid positivity, cognitive impairment, and CSF AD biomarkers. RESULTS: Cognitive impairment correlated with lower TB spectral power in SW-TB coupling. Cognitively unimpaired, amyloid positive individuals demonstrated lower precision in SW-TB and SW-SP coupling compared to amyloid negative individuals. Significant biomarker correlations were found in oscillatory event coupling with CSF Aß42 /Aß40 , phosphorylated- tau181 , and total-tau. DISCUSSION: Sleep-dependent memory processing integrity in neural circuits can be measured for both SW-TB and SW-SP coupling. This breakdown associates with amyloid positivity, increased AD pathology, and cognitive impairment. HIGHLIGHTS: At-home sleep EEG is a potential biomarker of neural circuits linked to memory. Circuit precision is associated with amyloid positivity in asymptomatic aging adults. Levels of CSF amyloid and tau also correlate with circuit precision in sleep EEG. Theta burst EEG power is decreased in very early mild cognitive impairment. This technique may enable inexpensive wearable EEGs for monitoring brain health.

The Effect of Hypoxia-inducible Factor Inhibition on the Phenotype of Fibroblasts in Human and Bovine Pulmonary Hypertension.

Hypoxia-inducible factor (HIF) has received much attention as a potential pulmonary hypertension (PH) treatment target because inhibition of HIF reduces the severity of established PH in rodent models. However, the limitations of small-animal models of PH in predicting the therapeutic effects of pharmacologic interventions in humans PH are well known. Therefore, we sought to interrogate the role of HIFs in driving the activated phenotype of PH cells from human and bovine vessels. We first established that pulmonary arteries (PAs) from human and bovine PH lungs exhibit markedly increased expression of direct HIF target genes (CA9, GLUT1, and NDRG1), as well as cytokines/chemokines (CCL2, CSF2, CXCL12, and IL6), growth factors (FGF1, FGF2, PDGFb, and TGFA), and apoptosis-resistance genes (BCL2, BCL2L1, and BIRC5). The expression of the genes found in the intact PAs was determined in endothelial cells, smooth muscle cells, and fibroblasts cultured from the PAs. The data showed that human and bovine pulmonary vascular fibroblasts from patients or animals with PH (termed PH-Fibs) were the cell type that exhibited the highest level and the most significant increases in the expression of cytokines/chemokines and growth factors. In addition, we found that human, but not bovine, PH-Fibs exhibit consistent misregulation of HIFα protein stability, reduced HIF1α protein hydroxylation, and increased expression of HIF target genes even in cells grown under normoxic conditions. However, whereas HIF inhibition reduced the expression of direct HIF target genes, it had no impact on other "persistently activated" genes. Thus, our study indicated that HIF inhibition alone is not sufficient to reverse the persistently activated phenotype of human and bovine PH-Fibs.

Functional and molecular determinants of right ventricular response to severe pulmonary hypertension in a large animal model.

Right ventricular (RV) failure is the major determinant of outcome in pulmonary hypertension (PH). Calves exposed to 2-wk hypoxia develop severe PH and unlike rodents, hypoxia-induced PH in this species can lead to right heart failure. We, therefore, sought to examine the molecular and structural changes in the RV in calves with hypoxia-induced PH, hypothesizing that we could identify mechanisms underlying compensated physiological function in the face of developing severe PH. Calves were exposed to 14 days of environmental hypoxia (equivalent to 4,570 m/15,000 ft elevation, n = 29) or ambient normoxia (1,525 m/5,000 ft, n = 25). Cardiopulmonary function was evaluated by right heart catheterization and pressure volume loops. Molecular and cellular determinants of RV remodeling were analyzed by cDNA microarrays, RealTime PCR, proteomics, and immunochemistry. Hypoxic exposure induced robust PH, with increased RV contractile performance and preserved cardiac output, yet evidence of dysregulated RV-pulmonary artery mechanical coupling as seen in advanced disease. Analysis of gene expression revealed cellular processes associated with structural remodeling, cell signaling, and survival. We further identified specific clusters of gene expression associated with 1) hypertrophic gene expression and prosurvival mechanotransduction through YAP-TAZ signaling, 2) extracellular matrix (ECM) remodeling, 3) inflammatory cell activation, and 4) angiogenesis. A potential transcriptomic signature of cardiac fibroblasts in RV remodeling was detected, enriched in functions related to cell movement, tissue differentiation, and angiogenesis. Proteomic and immunohistochemical analysis confirmed RV myocyte hypertrophy, together with localization of ECM remodeling, inflammatory cell activation, and endothelial cell proliferation within the RV interstitium. In conclusion, hypoxia and hemodynamic load initiate coordinated processes of protective and compensatory RV remodeling to withstand the progression of PH.NEW & NOTEWORTHY Using a large animal model and employing a comprehensive approach integrating hemodynamic, transcriptomic, proteomic, and immunohistochemical analyses, we examined the early (2 wk) effects of severe PH on the RV. We observed that RV remodeling during PH progression represents a continuum of transcriptionally driven processes whereby cardiac myocytes, fibroblasts, endothelial cells, and proremodeling macrophages act to coordinately maintain physiological homeostasis and protect myocyte survival during chronic, severe, and progressive pressure overload.

Characterizing the Spatiotemporal Transcriptomic Response of the Right Ventricle to Acute Pressure Overload.

This study analyzed microarray data of right ventricular (RV) tissue from rats exposed to pulmonary embolism to understand the initial dynamic transcriptional response to mechanical stress and compare it with experimental pulmonary hypertension (PH) models. The dataset included samples harvested from 55 rats at 11 different time points or RV locations. We performed principal component analysis (PCA) to explore clusters based on spatiotemporal gene expression. Relevant pathways were identified from fast gene set enrichment analysis using PCA coefficients. The RV transcriptomic signature was measured over several time points, ranging from hours to weeks after an acute increase in mechanical stress, and was found to be highly dependent on the severity of the initial insult. Pathways enriched in the RV outflow tracts of rats at 6 weeks after severe PE share many commonalities with experimental PH models, but the transcriptomic signature at the RV apex resembles control tissue. The severity of the initial pressure overload determines the trajectory of the transcriptomic response independent of the final afterload, but this depends on the location where the tissue is biopsied. Chronic RV pressure overload due to PH appears to progress toward similar transcriptomic endpoints.

Single-cell RNA sequencing and binary hierarchical clustering define lung interstitial macrophage heterogeneity in response to hypoxia.

Few studies have examined lung interstitial macrophage (IM) molecular phenotypes after being exposed to hypoxia in vivo at the single-cell level, even though macrophages contribute to hypoxic pulmonary hypertension (PH). We aimed to determine IM diversity and its association with hypoxia-induced PH. We hypothesized that integrating single-cell RNA sequencing (scRNAseq) and binary hierarchal clustering (BHC) could resolve IM heterogeneity under normal homeostatic conditions and changes induced by hypoxia exposure. Cx3cr1GFP/+ reporter mice were exposed to normoxic conditions (∼21% [Formula: see text]) or exposed to 1 day (D1) or 7 days (D7) of hypoxia (∼10% [Formula: see text]). We used flow cytometry to isolate Cx3cr1+ IMs and the 10X Genomics platform for scRNAseq, Cell Ranger, Seurat, ClusterMap, monocle, ingenuity pathway analysis, and Fisher's exact test (q value < 0.05) for functional investigations. n = 374 (normoxia), n = 2,526 (D1), and n = 1,211 (D7) IMs were included in the analyses. We identified three normoxia-related cell types, five hypoxia-associated cell types that emerged at D1, and three that appeared at D7. We describe the existence of a putative resident trained innate IM, which is present in normoxia, transiently depleted at D1, and recovered after 7 days of sustained hypoxia. We also define a rare putative pathogenic population associated with transcripts implicated in PH development that emerges at D7. In closing, we describe the successful integration of BHC with scRNAseq to determine IM heterogeneity and its association with PH. These results shed light on how resident-trained innate IMs become more heterogeneous but ultimately accustomed to hypoxia.

Hemodynamically Unloading the Distal Pulmonary Circulation in Pulmonary Hypertension: A Modeling Study.

Pulmonary hypertension (PH) is a progressive disease that is characterized by a gradual increase in both resistive and reactive pulmonary arterial (PA) impedance. Previous studies in a rodent model of PH have shown that reducing the hemodynamic load in the left lung (by banding the left PA) reverses this remodeling phenomenon. However, banding a single side of the pulmonary circulation is not a viable clinical option, so-using in silico modeling-we evaluated if the banding effect can be recreated by replacing the proximal vasculature with a compliant synthetic PA. We developed a computational model of the pulmonary circulation by combining a one-dimensional model of the proximal vasculature with a zero-dimensional line transmission model to the 12th generation. Using this model, we performed four simulations: (1) Control; (2) PH; (3) PH with a stenosis in the left PA; and (4) PH with proximal vessel compliance returned to Control levels. Simulations revealed that vascular changes associated with PH result in an increase in pulse pressure (PP), maximum pressure (Pmax), maximum wall shear stress (WSS), and maximum circumferential stress (σθθ) relative to controls, in the distal circulation. Banding the left PA reduced these measurements of hemodynamic stress in the left lung, but increases them in the right lung. Furthermore, left PA banding increased reactive PA impedance. However, returning the proximal PA compliance to Control levels simultaneously decreased all measures of hemodynamic stress in both lungs, and returned reactive PA impedance to normal levels. In conclusion, if future in vivo studies support the idea of hemodynamic unloading as an effective therapy for PH, this can be surgically achieved by replacing the proximal PA with a compliant prosthesis, and it will have the added benefit of reducing reactive right ventricular afterload.

Improving Right Ventricular Function by Increasing BMP Signaling with FK506.

Right ventricular (RV) function is the predominant determinant of survival in patients with pulmonary arterial hypertension (PAH). In preclinical models, pharmacological activation of BMP (bone morphogenetic protein) signaling with FK506 (tacrolimus) improved RV function by decreasing RV afterload. FK506 therapy further stabilized three patients with end-stage PAH. Whether FK506 has direct effects on the pressure-overloaded right ventricle is yet unknown. We hypothesized that increasing cardiac BMP signaling with FK506 improves RV structure and function in a model of fixed RV afterload after pulmonary artery banding (PAB). Direct cardiac effects of FK506 on the microvasculature and RV fibrosis were studied after surgical PAB in wild-type and heterozygous Bmpr2 mutant mice. RV function and strain were assessed longitudinally via cardiac magnetic resonance imaging during continuous FK506 infusion. Genetic lineage tracing of endothelial cells (ECs) was performed to assess the contribution of ECs to fibrosis. Molecular mechanistic studies were performed in human cardiac fibroblasts and ECs. In mice, low BMP signaling in the right ventricle exaggerated PAB-induced RV fibrosis. FK506 therapy restored cardiac BMP signaling, reduced RV fibrosis in a BMP-dependent manner independent from its immunosuppressive effect, preserved RV capillarization, and improved RV function and strain over the time course of disease. Endothelial mesenchymal transition was a rare event and did not significantly contribute to cardiac fibrosis after PAB. Mechanistically, FK506 required ALK1 in human cardiac fibroblasts as a BMPR2 co-receptor to reduce TGFß1-induced proliferation and collagen production. Our study demonstrates that increasing cardiac BMP signaling with FK506 improves RV structure and function independent from its previously described beneficial effects on pulmonary vascular remodeling.

Pulmonary arterial banding in mice may be a suitable model for studies on ventricular mechanics in pediatric pulmonary arterial hypertension.

BACKGROUND: The role of interventricular mechanics in pediatric pulmonary arterial hypertension (PAH) and its relation to right ventricular (RV) dysfunction has been largely overlooked. Here, we characterize the impact of maintained pressure overload in the RV-pulmonary artery (PA) axis on myocardial strain and left ventricular (LV) mechanics in pediatric PAH patients in comparison to a preclinical PA-banding (PAB) mouse model. We hypothesize that the PAB mouse model mimics important aspects of interventricular mechanics of pediatric PAH and may be beneficial as a surrogate model for some longitudinal and interventional studies not possible in children. METHODS: Balanced steady-state free precession (bSSFP) cardiovascular magnetic resonance (CMR) images of 18 PAH and 17 healthy (control) pediatric subjects were retrospectively analyzed using CMR feature-tracking (FT) software to compute measurements of myocardial strain. Furthermore, myocardial tagged-CMR images were also analyzed for each subject using harmonic phase flow analysis to derive LV torsion rate. Within 48 h of CMR, PAH patients underwent right heart catheterization (RHC) for measurement of PA/RV pressures, and to compute RV end-systolic elastance (RV_Ees, a measure of load-independent contractility). Surgical PAB was performed on mice to induce RV pressure overload and myocardial remodeling. bSSFP-CMR, tagged CMR, and intra-cardiac catheterization were performed on 12 PAB and 9 control mice (Sham) 7 weeks after surgery with identical post-processing as in the aforementioned patient studies. RV_Ees was assessed via the single beat method. RESULTS: LV torsion rate was significantly reduced under hypertensive conditions in both PAB mice (p = 0.004) and pediatric PAH patients (p < 0.001). This decrease in LV torsion rate correlated significantly with a decrease in RV_Ees in PAB (r = 0.91, p = 0.05) and PAH subjects (r = 0.51, p = 0.04). In order to compare combined metrics of LV torsion rate and strain parameters principal component analysis (PCA) was used. PCA revealed grouping of PAH patients with PAB mice and control subjects with Sham mice. Similar to LV torsion rate, LV global peak circumferential, radial, and longitudinal strain were significantly (p < 0.05) reduced under hypertensive conditions in both PAB mice and children with PAH. CONCLUSIONS: The PAB mouse model resembles PAH-associated myocardial mechanics and may provide a potential model to study mechanisms of RV/LV interdependency.

Structural and Biomechanical Adaptations of Right Ventricular Remodeling-In Pulmonary Arterial Hypertension-Reduces Left Ventricular Rotation During Contraction: A Computational Study.

Pulmonary hypertension (PH) is a degenerative disease characterized by progressively increased right ventricular (RV) afterload that leads to ultimate functional decline. Recent observational studies have documented a decrease in left ventricular (LV) torsion during ejection, with preserved LV ejection fraction (EF) in pediatric and adult PH patients. The objective of this study was to develop a computational model of the biventricular heart and use it to evaluate changes in LV torsion mechanics in response to mechanical, structural, and hemodynamic changes in the RV free wall. The heart model revealed that LV torsion and apical rotation were decreased when increasing RV mechanical rigidity and during re-orientation of RV myocardial fibers, both of which have been demonstrated in PH. Furthermore, structural changes to the RV appear to have a notable impact on RV EF, but little influence on LV EF. Finally, RV pressure overload exponentially increased LV myocardial stress. The computational results found in this study are consistent with clinical observations in adult and pediatric PH patients, which reveal a decrease in LV torsion with preserved LV EF. Furthermore, discovered causes of decreased LV torsion are consistent with RV structural adaptations seen in PH rodent studies, which might also explain suspected stress-induced changes in LV myocardial gene and protein expression.

Reduced shear stress and associated aortic deformation in the thoracic aorta of patients with chronic obstructive pulmonary disease.

OBJECTIVE: Central aortic stiffness and chronic obstructive pulmonary disease (COPD) are associated with increased incidence of devastating aortopathies. However, the exact mechanism leading to elevated aortic stiffness in patients with COPD is unknown. The purpose of this study was to quantify flow and shear hemodynamic indices, known markers of vascular remodeling, in the thoracic aorta of patients with mild to moderate COPD (n = 16) and to compare these results with an age-matched control group (n = 10). METHODS: Four-dimensional flow magnetic resonance imaging has been applied to measure hemodynamic wall shear stress (WSS) at four specific planes along the ascending aorta, aortic arch, and proximal descending aorta for all subjects. Peak systolic WSS and time-averaged WSS, which respectively reflect magnitude and temporal shear variability, were calculated at standardized planes. Aortic deformation was measured by means of relative area change (RAC) at the midlevel of the ascending and descending aorta. RESULTS: Compared with controls, patients with COPD had significantly reduced RAC in the mid ascending aorta (9% vs 18%; P < .0001) and descending aorta (15% vs 19%; P = .0206). Peak systolic WSS in COPD patients was significantly reduced in all considered planes, with the most dramatic difference occurring in the descending aorta (0.46 vs 0.86 N/m2; P < .0001). Peak systolic WSS and time-averaged WSS were both significantly correlated with aortic RAC at each evaluated plane. CONCLUSIONS: Reduced flow shear metrics assessed at specific aortic regions correlated with RAC, a marker of aortic stiffness. Reduced hemodynamic WSS may then contribute to central aortic stiffening and perpetuate the risk for development of severe aortopathy.

Measuring Flow Hemodynamic Indices and Oxygen Consumption in Children with Pulmonary Hypertension: A Comparison of Catheterization and Phase-Contrast MRI.

We sought to compare pulmonary flow hemodynamic indices obtained by Fick and thermodilution catheterization techniques with phase-contrast MRI (PC-MRI) in children with diverse etiologies of pulmonary arterial hypertension (PAH). Calculation of pulmonary flow ([Formula: see text]) using the Fick principle in most catheter laboratories relies on an estimate of oxygen consumption which may limit its reliability. Flow hemodynamic indices acquired from thirty patients with PAH who underwent successful same-day PC-MRI and catheterization were evaluated for absolute and percent bias. Comparison of [Formula: see text] between PC-MRI and Fick revealed poor agreement with an absolute bias of 0.96 ± 0.53 L/min/m2 and percent bias of 27.7 ± 19.6%. Same analysis between PC-MRI and thermodilution revealed better agreement as demonstrated by absolute bias 0.64 ± 0.47 L/min/m2 and percent bias 16.8 ± 12.3%. Retrospectively calculated [Formula: see text] from PC-MRI and LaFarge equations revealed poor agreement, with an absolute bias of 33.4 ± 21.6 mL/min/m2 and percent bias of 25.8 ± 12.6%. We found that Fick-derived flow hemodynamics dramatically differs from PC-MRI computed metrics in children with PAH. The non-invasive nature of PC-MRI and short acquisition time is ideal for pediatric flow evaluation and may offer a novel route of absolute flow and resistance assessment when combined with cardiac catheterization.

4D magnetic resonance flow imaging for estimating pulmonary vascular resistance in pulmonary hypertension.

PURPOSE: To develop an estimate of pulmonary vascular resistance (PVR) using blood flow measurements from 3D velocity-encoded phase contract magnetic resonance imaging (here termed 4D MRI). MATERIALS AND METHODS: In all, 17 patients with pulmonary hypertension (PH) and five controls underwent right heart catheterization (RHC), 4D and 2D Cine MRI (1.5T) within 24 hours. MRI was used to compute maximum spatial peak systolic vorticity in the main pulmonary artery (MPA) and right pulmonary artery (RPA), cardiac output, and relative area change in the MPA. These parameters were combined in a four-parameter multivariate linear regression model to arrive at an estimate of PVR. Agreement between model predicted and measured PVR was also evaluated using Bland-Altman plots. Finally, model accuracy was tested by randomly withholding a patient from regression analysis and using them to validate the multivariate equation. RESULTS: A decrease in vorticity in the MPA and RPA were correlated with an increase in PVR (MPA: R(2) = 0.54, P < 0.05; RPA: R(2) = 0.75, P < 0.05). Expanding on this finding, we identified a multivariate regression equation that accurately estimates PVR (R(2) = 0.94, P < 0.05) across severe PH and normotensive populations. Bland-Altman plots showed 95% of the differences between predicted and measured PVR to lie within 1.49 Wood units. Model accuracy testing revealed a prediction error of ∼20%. CONCLUSION: A multivariate model that includes MPA relative area change and flow characteristics, measured using 4D and 2D Cine MRI, offers a promising technique for noninvasively estimating PVR in PH patients. J. MAGN. RESON. IMAGING 2016;44:914-922.

A Zero-Dimensional Model and Protocol for Simulating Patient-Specific Pulmonary Hemodynamics From Limited Clinical Data.

In pulmonary hypertension (PH) diagnosis and management, many useful functional markers have been proposed that are unfeasible for clinical implementation. For example, assessing right ventricular (RV) contractile response to a gradual increase in pulmonary arterial (PA) impedance requires simultaneously recording RV pressure and volume, and under different afterload/preload conditions. In addition to clinical applications, many research projects are hampered by limited retrospective clinical data and could greatly benefit from simulations that extrapolate unavailable hemodynamics. The objective of this study was to develop and validate a 0D computational model, along with a numerical implementation protocol, of the RV-PA axis. Model results are qualitatively compared with published clinical data and quantitatively validated against right heart catheterization (RHC) for 115 pediatric PH patients. The RV-PA circuit is represented using a general elastance function for the RV and a three-element Windkessel initial value problem for the PA. The circuit mathematically sits between two reservoirs of constant pressure, which represent the right and left atriums. We compared Pmax, Pmin, mPAP, cardiac output (CO), and stroke volume (SV) between the model and RHC. The model predicted between 96% and 98% of the variability in pressure and 98-99% in volumetric characteristics (CO and SV). However, Bland Altman plots showed the model to have a consistent bias for most pressure and volumetric parameters, and differences between model and RHC to have considerable error. Future studies will address this issue and compare specific waveforms, but these initial results are extremely promising as preliminary proof of concept of the modeling approach.

A protocol for measuring pull-off stress of wound-treatment polymers.

Skin wounds and burns compromise the body's natural barrier to bacteria and other pathogens. While many forms of wound dressings are available, polymeric films are advantageous for various reasons, ranging from the ease of application to durability. One common drawback of using polymeric films for a wound bandage is that the films tend to adhere to common inanimate objects. Patients spend hours in contact with soft and hard materials pressed against their skin, which, if the skin was dressed with a polymeric film, would inflict further wound damage upon body movement. In this work, we present a novel technique that allowed for measuring polymeric tackiness, after a long incubation period, with materials regularly encountered in a hospital or home setting, and soft fabrics. The polymers were exposed to an environment intended to simulate daily conditions and the technique is designed to perform multiple experiments simultaneously with ease. Four commercially available polymers (new-skin, no-sting skin-prep, skin shield, and Silesse) were tested as proof-of-concept to gather preliminary data for an overall assessment of wound treatment efficacy, resulting in the estimation of pull-off stress of the polymers from a specimen of porcine skin. Silesse did not reveal a measurable tackiness, no-sting skin-prep had the highest mean tackiness (13.8 kPa), while the mean tackiness between new-skin and skin shield was approximately equal (9.8 kPa vs. 10.1 kPa, respectively), p = 0.05. Future work on polymeric fluids for wound dressing applications should include tensile stress and dynamic viscosity estimations.

Experimental and numerical models of three-dimensional gravity-driven flow of shear-thinning polymer solutions used in vaginal delivery of microbicides.

HIV/AIDS is a growing global pandemic. A microbicide is a formulation of a pharmaceutical agent suspended in a delivery vehicle, and can be used by women to protect themselves against HIV infection during intercourse. We have developed a three-dimensional (3D) computational model of a shear-thinning power-law fluid spreading under the influence of gravity to represent the distribution of a microbicide gel over the vaginal epithelium. This model, accompanied by a new experimental methodology, is a step in developing a tool for optimizing a delivery vehicle's structure/function relationship for clinical application. We compare our model with experiments in order to identify critical considerations for simulating 3D free-surface flows of shear-thinning fluids. Here we found that neglecting lateral spreading, when modeling gravity-induced flow, resulted in up to 47% overestimation of the experimental axial spreading after 90 s. In contrast, the inclusion of lateral spreading in 3D computational models resulted in rms errors in axial spreading under 7%. In addition, the choice of the initial condition for shape in the numerical simulation influences the model's ability to describe early time spreading behavior. Finally, we present a parametric study and sensitivity analysis of the power-law parameters' influence on axial spreading, and to examine the impact of changing rheological properties as a result of dilution or formulation conditions. Both the shear-thinning index (n) and consistency (m) impacted the spreading length and deceleration of the moving front. The sensitivity analysis showed that gels with midrange m and n values (for the ranges in this study) would be most sensitive (over 8% changes in spreading length) to 10% changes (e.g., from dilution) in both rheological properties. This work is applicable to many industrial and geophysical thin-film flow applications of non-Newtonian fluids; in addition to biological applications in microbicide drug delivery.

Variability of computational fluid dynamics solutions for pressure and flow in a giant aneurysm: the ASME 2012 Summer Bioengineering Conference CFD Challenge.

Stimulated by a recent controversy regarding pressure drops predicted in a giant aneurysm with a proximal stenosis, the present study sought to assess variability in the prediction of pressures and flow by a wide variety of research groups. In phase I, lumen geometry, flow rates, and fluid properties were specified, leaving each research group to choose their solver, discretization, and solution strategies. Variability was assessed by having each group interpolate their results onto a standardized mesh and centerline. For phase II, a physical model of the geometry was constructed, from which pressure and flow rates were measured. Groups repeated their simulations using a geometry reconstructed from a micro-computed tomography (CT) scan of the physical model with the measured flow rates and fluid properties. Phase I results from 25 groups demonstrated remarkable consistency in the pressure patterns, with the majority predicting peak systolic pressure drops within 8% of each other. Aneurysm sac flow patterns were more variable with only a few groups reporting peak systolic flow instabilities owing to their use of high temporal resolutions. Variability for phase II was comparable, and the median predicted pressure drops were within a few millimeters of mercury of the measured values but only after accounting for submillimeter errors in the reconstruction of the life-sized flow model from micro-CT. In summary, pressure can be predicted with consistency by CFD across a wide range of solvers and solution strategies, but this may not hold true for specific flow patterns or derived quantities. Future challenges are needed and should focus on hemodynamic quantities thought to be of clinical interest.

Gravity-Driven Thin Film Flow of an Ellis Fluid.

The thin film lubrication approximation has been studied extensively for moving contact lines of Newtonian fluids. However, many industrial and biological applications of the thin film equation involve shear-thinning fluids, which often also exhibit a Newtonian plateau at low shear. This study presents new numerical simulations of the three-dimensional (i.e. two-dimensional spreading), constant-volume, gravity-driven, free surface flow of an Ellis fluid. The numerical solution was validated with a new similarity solution, compared to previous experiments, and then used in a parametric study. The parametric study centered around rheological data for an example biological application of thin film flow: topical drug delivery of anti-HIV microbicide formulations, e.g. hydroxyethylcellulose (HEC) polymer solutions. The parametric study evaluated how spreading length and front velocity saturation depend on Ellis parameters. A lower concentration polymer solution with smaller zero shear viscosity (η0), τ1/2, and λ values spread further. However, when comparing any two fluids with any possible combinations of Ellis parameters, the impact of changing one parameter on spreading length depends on the direction and magnitude of changes in the other two parameters. In addition, the isolated effect of the shear-thinning parameter, λ, on the front velocity saturation depended on τ1/2. This study highlighted the relative effects of the individual Ellis parameters, and showed that the shear rates in this flow were in both the shear-thinning and plateau regions of rheological behavior, emphasizing the importance of characterizing the full range of shear-rates in rheological measurements. The validated numerical model and parametric study provides a useful tool for future steps to optimize flow of a fluid with rheological behavior well-described by the Ellis constitutive model, in a range of industrial and biological applications.