Efficient Uncertainty Quantification in a Multiscale Model of Pulmonary Arterial and Venous Hemodynamics.

Computational hemodynamics models are becoming increasingly useful in the management and prognosis of complex, multiscale pathologies, including those attributed to the development of pulmonary vascular disease. However, diseases like pulmonary hypertension are heterogeneous, and affect both the proximal arteries and veins as well as the microcirculation. Simulation tools and the data used for model calibration are also inherently uncertain, requiring a full analysis of the sensitivity and uncertainty attributed to model inputs and outputs. Thus, this study quantifies model sensitivity and output uncertainty in a multiscale, pulse-wave propagation model of pulmonary hemodynamics. Our pulmonary circuit model consists of fifteen proximal arteries and twelve proximal veins, connected by a two-sided, structured tree model of the distal vasculature. We use polynomial chaos expansions to expedite the sensitivity and uncertainty quantification analyses and provide results for both the proximal and distal vasculature. Our analyses provide uncertainty in blood pressure, flow, and wave propagation phenomenon, as well as wall shear stress and cyclic stretch, both of which are important stimuli for endothelial cell mechanotransduction. We conclude that, while nearly all the parameters in our system have some influence on model predictions, the parameters describing the density of the microvascular beds have the largest effects on all simulated quantities in both the proximal and distal circulation.

Biventricular Interaction During Acute Left Ventricular Ischemia in Mice: A Combined In-Vivo and In-Silico Approach.

Computational models provide an efficient paradigm for integrating and linking multiple spatial and temporal scales. However, these models are difficult to parameterize and match to experimental data. Recent advances in both data collection and model analyses have helped overcome this limitation. Here, we combine a multiscale, biventricular interaction model with mouse data before and after left ventricular (LV) ischemia. Sensitivity analyses are used to identify the most influential parameters on pressure and volume predictions. The subset of influential model parameters are calibrated to biventricular pressure-volume loop data (n = 3) at baseline. Each mouse underwent left anterior descending coronary artery ligation, during which changes in fractional shortening and RV pressure-volume dynamics were recorded. Using the calibrated model, we simulate acute LV ischemia and contrast outputs at baseline and in simulated ischemia. Our baseline simulations align with the LV and RV data, and our predictions during ischemia complement recorded RV data and prior studies on LV function during myocardial infarction. We show that a model with both biventricular mechanical interaction and systems-level cardiovascular dynamics can quantitatively reproduce in-vivo data and qualitatively match prior findings from animal studies on LV ischemia.

Biventricular interaction during acute left ventricular ischemia in mice: a combined in-vivo and in-silico approach.

Computational models provide an efficient paradigm for integrating and linking multiple spatial and temporal scales. However, these models are difficult to parameterize and match to experimental data. Recent advances in both data collection and model analyses have helped overcome this limitation. Here, we combine a multiscale, biventricular interaction model with mouse data before and after left ventricular (LV) ischemia. Sensitivity analyses are used to identify the most influential parameters on pressure and volume predictions. The subset of influential model parameters are calibrated to biventricular pressure-volume loop data (n=3) at baseline. Each mouse underwent left anterior descending coronary artery ligation, during which changes in fractional shortening and RV pressure-volume dynamics were recorded. Using the calibrated model, we simulate acute LV ischemia and contrast outputs at baseline and in simulated ischemia. Our baseline simulations align with the LV and RV data, and our predictions during ischemia complement recorded RV data and prior studies on LV function during myocardial infarction. We show that a model with both biventricular mechanical interaction and systems level cardiovascular dynamics can quantitatively reproduce in-vivo data and qualitatively match prior findings from animal studies on LV ischemia.

Increased length-dependent activation of human engineered heart tissue after chronic α1A-adrenergic agonist treatment: testing a novel heart failure therapy.

Chronic stimulation of cardiac α1A-adrenergic receptors (α1A-ARs) improves symptoms in multiple preclinical models of heart failure. However, the translational significance remains unclear. Human engineered heart tissues (EHTs) provide a means of quantifying the effects of chronic α1A-AR stimulation on human cardiomyocyte physiology. EHTs were created from thin slices of decellularized pig myocardium seeded with human induced pluripotent stem cell (iPSC)-derived cardiomyocytes and fibroblasts. With a paired experimental design, EHTs were cultured for 3 wk, mechanically tested, cultured again for 2 wk with α1A-AR agonist A61603 (10 nM) or vehicle control, and retested after drug washout for 24 h. Separate control experiments determined the effects of EHT age (3-5 wk) or repeat mechanical testing. We found that chronic A61603 treatment caused a 25% increase of length-dependent activation (LDA) of contraction compared with vehicle treatment (n = 7/group, P = 0.035). EHT force was not increased after chronic A61603 treatment. However, after vehicle treatment, EHT force was increased by 35% relative to baseline testing (n = 7/group, P = 0.022), suggesting EHT maturation. Control experiments suggested that increased EHT force resulted from repeat mechanical testing, not from EHT aging. RNA-seq analysis confirmed that the α1A-AR is expressed in human EHTs and found chronic A61603 treatment affected gene expression in biological pathways known to be activated by α1A-ARs, including the MAP kinase signaling pathway. In conclusion, increased LDA in human EHT after chronic A61603 treatment raises the possibility that chronic stimulation of the α1A-AR might be beneficial for increasing LDA in human myocardium and might be beneficial for treating human heart failure by restoring LDA.NEW & NOTEWORTHY Chronic stimulation of α1A-adrenergic receptors (α1A-ARs) is known to mediate therapeutic effects in animal heart failure models. To investigate the effects of chronic α1A-AR stimulation in human cardiomyocytes, we tested engineered heart tissue (EHT) created with iPSC-derived cardiomyocytes. RNA-seq analysis confirmed human EHT expressed α1A-ARs. Chronic (2 wk) α1A-AR stimulation with A61603 (10 nM) increased length-dependent activation (LDA) of contraction. Chronic α1A-AR stimulation might be beneficial for treating human heart failure by restoring LDA.

Effects of Red Blood Cell Sickling on Right Ventricular Afterload in vivo.

BACKGROUND: Hemolysis in sickle cell disease (SCD) releases cell free hemoglobin, which scavenges nitric oxide (NO), leading to pulmonary vascular vasoconstriction, increased pulmonary vascular resistance (PVR), and the development of PH. However, PVR is only one component of right ventricular (RV) afterload. Whether sickled red blood cells increase the total RV afterload, including compliance and wave reflections, is unclear. OBJECTIVE: Patients with SCD and pulmonary hypertension (PH) have a significantly increased risk of sudden death compared to patients with SCD alone. Sickled red blood cells (RBCs) are fragile and lyse easily. Here, we sought to determine the acute effects of SCD RBCs and increased cell free hemoglobin on RV afterload. METHODS: Main pulmonary artery pressures and flows were measured in C57BL6 mice before and after exchanges of whole blood (~200 uL, Hct=45%) with an equal volume of SCD RBCs in plasma (Hct=45%) or cell free hemoglobin (Hb+) in solution. After transfusions, animals were additionally stressed with acute hypoxia (AH; 10% O2). RESULTS: SCD RBCs increased PVR only compared to control RBCs; cell free hemoglobin increased PVR and wave reflections. These increases in RV afterload increased further with AH. CONCLUSIONS: The release of cell free hemoglobin from fragile SCD RBCs in vivo increases the total RV afterload and may impair RV function more than the SCD RBCs themselves.

Susceptibility to high-altitude pulmonary edema is associated with increased pulmonary arterial stiffness during exercise.

High-altitude pulmonary edema (HAPE), a reversible form of capillary leak, is a common consequence of rapid ascension to high altitude and a major cause of death related to high-altitude exposure. Individuals with a prior history of HAPE are more susceptible to future episodes, but the underlying risk factors remain uncertain. Previous studies have shown that HAPE-susceptible subjects have an exaggerated pulmonary vasoreactivity to acute hypoxia, but incomplete data are available regarding their vascular response to exercise. To examine this, seven HAPE-susceptible subjects and nine control subjects (HAPE-resistant) were studied at rest and during incremental exercise at sea level and at 3,810 m altitude. Studies were conducted in both normoxic (inspired Po2 = 148 Torr) and hypoxic (inspired Po2 = 91 Torr) conditions at each location. Here, we report an expanded analysis of previously published data, including a distensible vessel model that showed that HAPE-susceptible subjects had significantly reduced small distal artery distensibility at sea level compared with HAPE-resistant control subjects [0.011 ± 0.001 vs. 0.021 ± 0.002 mmHg-1; P < 0.001). Moreover, HAPE-susceptible subjects demonstrated constant distensibility over all conditions, suggesting that distal arteries are maximally distended at rest. Consistent with having increased distal artery stiffness, HAPE-susceptible subjects had greater increases in pulmonary artery pulse pressure with exercise, which suggests increased proximal artery stiffness. In summary, HAPE-susceptible subjects have exercise-induced increases in proximal artery stiffness and baseline increases in distal artery stiffness, suggesting increased pulsatile load on the right ventricle.NEW & NOTEWORTHY In comparison to subjects who appear resistant to high-altitude pulmonary edema, those previously symptomatic show greater increases in large and small artery stiffness in response to exercise. These differences in arterial stiffness may be a risk factor for the development of high-altitude pulmonary edema or evidence that consequences of high-altitude pulmonary edema are long-lasting after return to sea level.

What does the time constant of the pulmonary circulation tell us about the progression of right ventricular dysfunction in pulmonary arterial hypertension?

Compliance (C) and resistance (R) maintain a unique, inverse relationship in the pulmonary circulation, resulting in a constant characteristic time [Formula: see text] that has been observed in healthy subjects as well as patients with pulmonary arterial hypertension (PAH). However, little is known about the dependence of right ventricular (RV) function on the coupled changes in R and C in the context of this inverse relationship. We hypothesized three simple dependencies of RV ejection fraction (RVEF) on R and C. The first model (linear-R) assumes a linear RVEF-R relation; the second (linear-C) assumes a linear RVEF-C relation; and the third one combines the former two in a mixed linear model. We found that the linear-R model and the mixed linear model are in good agreement with clinical evidence. A conclusive validation of these models will require more clinical data. Longitudinal data in particular are needed to identify the time course of ventricular-vascular impairment in PAH. Simple models like the ones we present here, once validated, will advance our understanding of the mechanisms of RV failure, which could improve strategies to manage RV dysfunction in PAH.

A novel in vivo approach to assess radial and axial distensibility of large and intermediate pulmonary artery branches.

Pulmonary arteries (PAs) distend to accommodate increases in cardiac output. PA distensibility protects the right ventricle (RV) from excessive increases in pressure. Loss of PA distensibility plays a critical role in the fatal progression of pulmonary arterial hypertension (PAH) toward RV failure. However, it is unclear how PA distensibility is distributed across the generations of PA branches, mainly because of the lack of appropriate in vivo methods to measure distensibility of vessels other than the large, conduit PAs. In this study, we propose a novel approach to assess the distensibility of individual PA branches. The metric of PA distensibility we used is the slope of the stretch ratio-pressure relationship. To measure distensibility, we combined invasive measurements of mean PA pressure with angiographic imaging of the PA network of six healthy female dogs. Stacks of 2D images of the PAs, obtained from either contrast enhanced magnetic resonance angiography (CE-MRA) or computed tomography digital subtraction angiography (CT-DSA), were used to reconstruct 3D surface models of the PA network, from the first bifurcation down to the sixth generation of branches. For each branch of the PA, we calculated radial and longitudinal stretch between baseline and a pressurized state obtained via acute embolization of the pulmonary vasculature. Our results indicated that large and intermediate PA branches have a radial distensibility consistently close to 2%/mmHg. Our axial distensibility data, albeit affected by larger variability, suggested that the PAs distal to the first generation may not significantly elongate in vivo, presumably due to spatial constraints. Results from both angiographic techniques were comparable to data from established phase-contrast (PC) magnetic resonance imaging (MRI) and ex vivo mechanical tests, which can only be used in the first branch generation. Our novel method can be used to characterize PA distensibility in PAH patients undergoing clinical right heart catheterization (RHC) in combination with MRI.

Pulmonary circulation at exercise.

The pulmonary circulation is a high-flow and low-pressure circuit, with an average resistance of 1 mmHg/min/L in young adults, increasing to 2.5 mmHg/min/L over four to six decades of life. Pulmonary vascular mechanics at exercise are best described by distensible models. Exercise does not appear to affect the time constant of the pulmonary circulation or the longitudinal distribution of resistances. Very high flows are associated with high capillary pressures, up to a 20 to 25 mmHg threshold associated with interstitial lung edema and altered ventilation/perfusion relationships. Pulmonary artery pressures of 40 to 50 mmHg, which can be achieved at maximal exercise, may correspond to the extreme of tolerable right ventricular afterload. Distension of capillaries that decrease resistance may be of adaptative value during exercise, but this is limited by hypoxemia from altered diffusion/perfusion relationships. Exercise in hypoxia is associated with higher pulmonary vascular pressures and lower maximal cardiac output, with increased likelihood of right ventricular function limitation and altered gas exchange by interstitial lung edema. Pharmacological interventions aimed at the reduction of pulmonary vascular tone have little effect on pulmonary vascular pressure-flow relationships in normoxia, but may decrease resistance in hypoxia, unloading the right ventricle and thereby improving exercise capacity. Exercise in patients with pulmonary hypertension is associated with sharp increases in pulmonary artery pressure and a right ventricular limitation of aerobic capacity. Exercise stress testing to determine multipoint pulmonary vascular pressures-flow relationships may uncover early stage pulmonary vascular disease.

Exercise stress echocardiography for the study of the pulmonary circulation.

Exercise stress tests have been used for the diagnosis of pulmonary hypertension, but with variable protocols and uncertain limits of normal. The pulmonary haemodynamic response to progressively increased workload and recovery was investigated by Doppler echocardiography in 25 healthy volunteers aged 19-62 yrs (mean 36 yrs). Mean pulmonary artery pressure ((Ppa)) was estimated from the maximum velocity of tricuspid regurgitation. Cardiac output (Q) was calculated from the aortic velocity-time integral. Slopes and extrapolated pressure intercepts of (Ppa)-Q plots were calculated after using the adjustment of Poon for individual variability. A pulmonary vascular distensibility alpha was calculated from each (Ppa)-Q plot to estimate compliance. (Ppa) increased from 14+/-3 mmHg to 30+/-7 mmHg, and decreased to 19+/-4 mmHg after 5 min recovery. The slope of (Ppa)-Q was 1.37+/-0.65 mmHg x min(-1) x L(-1) with an extrapolated pressure intercept of 8.2+/-3.6 mmHg and an alpha of 0.017+/-0.018 mmHg(-1). These results agree with those of previous invasive studies. Multipoint (pa)-Q plots were well described by a linear approximation, from which resistance can be calulated. We conclude that exercise echocardiography of the pulmonary circulation is feasible and provides realistic resistance and compliance estimations. Measurements during recovery are unreliable because of rapid return to baseline.

Characterization of CSF hydrodynamics in the presence and absence of tonsillar ectopia by means of computational flow analysis.

BACKGROUND AND PURPOSE: Phase-contrast MR imaging (PCMR) has only partially characterized cyclic CSF flow and pressure, which, hypothetically, have a role in the pathogenesis of syrinx and symptoms in the Chiari I malformation. Our goal was to use computational flow analysis (CFA) to better understand CSF hydrodynamics. MATERIALS AND METHODS: High-resolution MR images were obtained in a healthy volunteer and a patient with Chiari I malformation. With standard segmentation and discretization techniques, 3D models of the subarachnoid space, cerebellum, and spinal canal were created. CSF flow during systole and diastole were simulated with the boundary element method in the models. CSF velocities and pressures computed in the patient with Chiari I malformation were compared with those in the healthy volunteer. Flow patterns were also compared with PCMR results for validation of the technique. RESULTS: The CFA and PCMR results agreed well. Inhomogeneous flow patterns characterized by fluid jets anterior and lateral to the spinal cord were demonstrated in both the Chiari I and volunteer models by CFA. Significant circumferential velocities were evident, suggesting swirling flow in the spinal canal. Higher magnitude jets were found in the patient with Chiari I than in the healthy volunteer. Relatively even pressure gradients were found along the spinal canal in both cases, with a 50% steeper gradient in the patient with Chiari I malformation. CONCLUSIONS: Circumferential velocities and pressure gradients in the spinal canal, which may be clinically relevant to Chiari I and other malformations, can be obtained by CFA in patient-specific geometries.

Early effects of arterial hemodynamic conditions on human saphenous veins perfused ex vivo.

Exposure to the arterial hemodynamic environment is thought to be a potential trigger for the pathological remodeling of saphenous vein grafts. Using matched pairs of freshly isolated human saphenous vein, we analyzed the early effects of ex vivo hemodynamic conditions mimicking the venous (native) compared with arterial (graft) environment on the key components of vascular remodeling, ie, matrix metalloproteinase (MMP)-9 and MMP-2 and cell proliferation. Interestingly, we found that arterial conditions halved latent MMP-9 (50+/-11%, P=0.01) and MMP-2 (44+/-6%, P=0.005) levels relative to matched vein pairs maintained ex vivo under venous perfusion for up to 3 days. Immunostaining supported decreased MMP levels in the innermost area of arterially perfused veins. Either decreased synthesis or increased posttranslational processing may decrease MMP zymogen levels. Biosynthetic radiolabeling showed that arterial perfusion actually increased MMP-9 and MMP-2 production. When we then examined potential pathways for MMP zymogen processing, we found that arterial conditions did not affect the expression of MT-MMP-1, a cell-associated MMP activator, but that they significantly increased the levels of superoxide, another MMP activator, suggesting redox-dependent MMP processing. Additional experiments indicated that increased superoxide under arterial conditions was due to diminished scavenging by decreased extracellular superoxide dismutase. Arterial perfusion also stimulated cell proliferation (by 220% to 750%) in the majority of vein segments investigated. Our observations support the hypothesis that arterial hemodynamic conditions stimulate early vein graft remodeling. Furthermore, physiological arterial flow may work to prevent pathological remodeling, particularly the formation of intimal hyperplasia, through rapid inactivation of secreted MMPs and, possibly, through preferential stimulation of cell proliferation in the outer layers of the vein wall.

Transmural pressure induces matrix-degrading activity in porcine arteries ex vivo.

Extracellular matrix components must be degraded and resynthesized for vascular remodeling to occur. We hypothesized that the hemodynamic environment regulates activity of matrix metalloproteinases (MMPs), the primary agents for in vivo matrix degradation, during vascular remodeling in response to changes in transmural pressure and shear stress. Pathological hemodynamic conditions were reproduced in an ex vivo system in which we maintained porcine carotid arteries for 24 and 48 h. Total levels of MMP-2 and MMP-9 extracted from tissue homogenates and analyzed by SDS-PAGE zymography were stimulated by transmural pressure and were unaffected by shear stress changes. Degradation of two specific gelatinase substrates, gelatin and elastin, increased with increasing pressure, but the degradation was not affected by shear stress changes in tissue specimens analyzed using in situ zymography (gelatin) and fluorescent measurement of endogenous elastin degradation (elastin). Our results suggest that transmural pressure activates at least two members of the MMP family and that activity of these enzymes is accompanied by degradation of matrix components, effects that may be implicated in hypertensive vascular remodeling.

Performance analysis of a cardiac assist device in counterpulsation.

Performance of a cardiac assist device pumping chamber in counterpulsation was evaluated using numerical simulations of the unsteady, three-dimensional flow inside the chamber and an analytical model of the force required to eject and fill the chamber. The wall shear stress within the device was similarly computed and modeled. The analytical model was scaled to match the numerical results and then used to predict performance at physiological operating conditions. According to these models for a stroke volume of 70 ml, between 0.4 and 1.0 W is required for counterpulsation at a frequency of 1.33 Hz against a restorative spring, depending on the spring constant chosen. The power and the maximum force calculated are within the ranges a trained skeletal muscle is capable of providing. Shear stress predictions show that platelet activation in the absence of surface effects and hemolysis due to high shear are unlikely to occur with this design. Furthermore, vortices that develop in the chamber during filling are predicted to increase blood mixing and provide favorable washing of the chamber walls. A computational-analytical approach such as this may have potential to aid rapid performance evaluation of new devices and streamline the design optimization process.

Surface EMG as a fatigue indicator during FES-induced isometric muscle contractions.

The electromyogram (EMG) signal has potential as an indicator of stimulated muscle fatigue in applications of functional electrical stimulation (FES). In particular, it could be used to detect near lower limb collapse due to the associated muscle fatigue in FES-aided standing systems and thereby prevent falling. Surface EMG measurement, however, is hampered by stimulation artifact during FES. Modified surface stimulation and EMG detection equipment were designed and built to minimize this artifact and to permit detection of the electrical signal generated by the muscle during contraction. Artifact reduction techniques included shorting stimulator output leads between stimulus pulses and limiting and blanking slew rate in the EMG processing stage. Isometric fatigue experiments were performed by stimulating the quadriceps muscle of 20 able-bodied (a total of 125 trials) and three spinal cord injured (18 trials) subjects. Fatigue-tracking performance indicators were derived from the root-mean-square (RMS) of the EMG amplitude and from the median frequency (MF) of the EMG power spectral content. The results demonstrate that reliable fatigue tracking indicators for practical FES applications will be difficult to obtain, but that amplitude-based measures in spinal cord injured subjects show promise.

Fetal valproate syndrome: clinical and neuro-developmental features in two sibling pairs.

The clinical and neurodevelopmental features are presented of four children--two sibling pairs--who were exposed in utero to valproic acid. One of each pair of children presented for diagnosis and assessment of developmental delay; the other sibling was examined at a later date. Three of the children were globally developmentally delayed with marked speech disability, and had dysmorphic features consistent with fetal valproate syndrome. One also had features of infantile autism. The fourth child had some of the dysmorphic features connected with fetal valproate syndrome, but had normal intellect, with his verbal ability being significantly below his non-verbal ability. He currently attends a school for learning-disabled children.