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.Comment: 10 Figures, 2 table

Viscoelastic Properties of Cardiovascular Tissues

The aims of this chapter are to review the current state of knowledge regarding the viscoelastic behavior of cardiovascular tissues. We begin with a brief, general discussion of measurement and modeling of cardiovascular tissue viscoelasticity. We then review known viscoelastic behavior of arteries, veins, capillaries, blood components, the heart, and lymphatics. For each tissue type, we highlight tissue-specific measurement methods, the cellular and extracellular components responsible for tissue viscoelasticity, and the clinical implications of energy loss due to viscoelasticity. We conclude with a summary and suggestions for future research

Persistent Vascular Collagen Accumulation Alters Hemodynamic Recovery from Chronic Hypoxia

Pulmonary arterial hypertension (PAH) is caused by narrowing and stiffening of the pulmonary arteries that increase pulmonary vascular impedance (PVZ). In particular, small arteries narrow and large arteries stiffen. Large pulmonary artery (PA) stiffness is the best current predictor of mortality from PAH. We have previously shown that collagen accumulation leads to extralobar PA stiffening at high strain (Ooi et al. 2010). We hypothesized that collagen accumulation would increase PVZ, including total pulmonary vascular resistance (Z0), characteristic impedance (ZC), pulse wave velocity (PWV) and index of global wave reflections (Pb/Pf), which contribute to increased right ventricular afterload. We tested this hypothesis by exposing mice unable to degrade type I collagen (Col1a1R/R) to 21 days of hypoxia (hypoxia), some of which were allowed to recover for 42 days (recovery). Littermate wild-type mice (Col1a1+/+) were used as controls. In response to hypoxia, mean PA pressure (mPAP) increased in both mouse genotypes with no changes in cardiac output (CO) or PA inner diameter (ID); as a consequence, Z0 (mPAP/CO) increased by ∼100% in both genotypes (pZC, PWV and Pb/Pf did not change. However, with recovery, ZC and PWV decreased in the Col1a1+/+ mice and remained unchanged in the Col1a1R/R mice. Z0 decreased with recovery in both genotypes. Microcomputed tomography measurements of large PAs did not show evidence of stiffness changes as a function of hypoxia exposure or genotype. We conclude that hypoxia-induced PA collagen accumulation does not affect the pulsatile components of pulmonary hemodynamics but that excessive collagen accumulation does prevent normal hemodynamic recovery, which may have important consequences for right ventricular function

Dobutamine stress MRI in pulmonary hypertension: relationships between stress pulmonary artery relative area change, RV performance, and 10-year survival

In pulmonary hypertension (PH), right ventricular (RV) performance determines survival. Pulmonary artery (PA) stiffening is an important biomechanical event in PH and also predicts survival based on the PA relative area change (RAC) measured at rest using magnetic resonance imaging (MRI). In this exploratory study, we sought to generate novel hypotheses regarding the influence of stress RAC on PH prognosis and the interaction between PA stiffening, RV performance and survival. Fifteen PH patients underwent dobutamine stress-MRI (ds-MRI) and right heart catheterization. RACREST, RACSTRESS, and ΔRAC (RAC STRESS – RAC REST) were correlated against resting invasive hemodynamics and ds-MRI data regarding RV performance and RV-PA coupling efficiency (n’vv [RV stroke volume/RV end-systolic volume]). The impact of RAC, RV data, and n’vv on ten-year survival were determined using Kaplan–Meier analysis. PH patients with a low ΔRAC (<−2.6%) had a worse long-term survival (log-rank P = 0.045, HR for death = 4.46 [95% CI = 1.08–24.5]) than those with ΔRAC ≥ −2.6%. Given the small sample, these data should be interpreted with caution; however, low ΔRAC was associated with an increase in stress diastolic PA area indicating proximal PA stiffening. Associations of borderline significance were observed between low RACSTRESS and low n’vvSTRESS, Δη’VV, and ΔRVEF. Further studies are required to validate the potential prognostic impact of ΔRAC and the biomechanics potentially connecting low ΔRAC to shorter survival. Such studies may facilitate development of novel PH therapies targeted to the proximal PA

Data‐enabled cognitive modeling: Validating student engineers’ fuzzy design‐based decision‐making in a virtual design problem

The ability of future engineering professionals to solve complex real‐world problems depends on their design education and training. Because engineers engage with open‐ended problems in which there are unknown parameters and multiple competing objectives, they engage in fuzzy decision‐making, a method of making decisions that takes into account inherent imprecisions and uncertainties in the real world. In the design‐based decision‐making field, few studies have applied fuzzy decision‐making models to actual decision‐making process data. Thus, in this study, we use datasets on student decision‐making processes to validate approximate fuzzy models of student decision‐making, which we call data‐enabled cognitive modeling. The results of this study (1) show that simulated design problems provide rich datasets that enable analysis of student design decision‐making and (2) validate models of student design cognition that can inform future design curricula and help educators understand how students think about design problems

Impaired Myofilament Contraction Drives Right Ventricular Failure Secondary to Pressure Overload: Model Simulations, Experimental Validation, and Treatment Predictions

Introduction: Pulmonary hypertension (PH) causes pressure overload leading to right ventricular failure (RVF). Myocardial structure and myocyte mechanics are altered in RVF but the direct impact of these cellular level factors on organ level function remain unclear. A computational model of the cardiovascular system that integrates cellular function into whole organ function has recently been developed. This model is a useful tool for investigating how changes in myocyte structure and mechanics contribute to organ function. We use this model to determine how measured changes in myocyte and myocardial mechanics contribute to RVF at the organ level and predict the impact of myocyte-targeted therapy.Methods: A multiscale computational framework was tuned to model PH due to bleomycin exposure in mice. Pressure overload was modeled by increasing the pulmonary vascular resistance (PVR) and decreasing pulmonary artery compliance (CPA). Myocardial fibrosis and the impairment of myocyte maximum force generation (Fmax) were simulated by increasing the collagen content (↑PVR + ↓CPA + fibrosis) and decreasing Fmax (↑PVR + ↓CPA + fibrosis + ↓Fmax). A61603 (A6), a selective α1A-subtype adrenergic receptor agonist, shown to improve Fmax was simulated to explore targeting myocyte generated Fmax in PH.Results: Increased afterload (RV systolic pressure and arterial elastance) in simulations matched experimental results for bleomycin exposure. Pressure overload alone (↑PVR + ↓CPA) caused decreased RV ejection fraction (EF) similar to experimental findings but preservation of cardiac output (CO). Myocardial fibrosis in the setting of pressure overload (↑PVR + ↓PAC + fibrosis) had minimal impact compared to pressure overload alone. Including impaired myocyte function (↑PVR + ↓PAC + fibrosis + ↓Fmax) reduced CO, similar to experiment, and impaired EF. Simulations predicted that A6 treatment preserves EF and CO despite maintained RV pressure overload.Conclusion: Multiscale computational modeling enabled prediction of the contribution of cellular level changes to whole organ function. Impaired Fmax is a key feature that directly contributes to RVF. Simulations further demonstrate the therapeutic benefit of targeting Fmax, which warrants additional study. Future work should incorporate growth and remodeling into the computational model to enable prediction of the multiscale drivers of the transition from dysfunction to failure

Innovative Design within the Context of Virtual Internships: How Can It Be Defined and How is It Related to the Student Design Process?

Definitions of “innovative design” vary among authors and fields of study. This makes it difficult to establish how to determine innovative designs in new design environments, such as in a virtual internship environment. Nephrotex is a virtual internship which encourages players, who assume the role of virtual interns within the game, to fully explore a constrained design space with the goal of producing an optimized dialysis membrane. As a useful starting point for our definition of “innovative design” within this design environment, we referenced the work of Baregheh et al. (2009) and formed the following definition: “A process that not only leads to unique physical or technical product attributes but also adds value beyond existing designs on the market.” We defined uniqueness based on the design occurring infrequently amongst the final products of student design teams. Quality was assessed based on the work of Arastoopour and colleagues (2014), taking technical and economic performance into consideration to determine how well the design was able to meet the Nephrotex internal consultant requirements for the design. Using this definition, we sought to answer the following research question: How does the design process differ for a team that generates an innovative vs. non-innovative design within a virtual internship? Specifically, do innovative teams report more frequently that they spend the most time on certain design activities (grouped using Dym’s design framework) versus non-innovative teams? Further, do innovative teams make their final design justifications on the basis of different factors than non-innovative teams do? This research was conducted with sophomore chemical engineering students in the spring 2014 and 2015 semesters. A total of 50 teams of approximately 4-5 students each were studied. Student design processes were evaluated based on innovativeness as well as weekly journal entries where students reported the three activities they spent the most time on. Our results showed no significant differences between innovative and non-innovative teams in terms of their reports of the Dym’s-based activities that they spent the most time on, although our sample size was small. The Management category was associated with the largest effect size (d=0.68), with innovative teams reporting more frequently than non-innovative teams that they spent the most time on design activities that were Management-related. In terms of attributes that contributed to innovative products, teams with higher innovation scores tended to prioritize cost and membrane efficiency (as determined by maximum allowable flux) over patient comfort (measured by blood cell reactivity) and projected market sales. Our results are intended to provide a map for design processes that may ultimately lead to more innovative designs within a virtual internship environment