Daniela Valdez-Jasso

Analysis of Viscoelastic Wall Properties in Ovine Arteries

In this paper, we analyze how elastic and viscoelastic properties differ across seven locations along the large arteries in 11 sheep. We employ a two-parameter elastic model and a four-parameter Kelvin viscoelastic model to analyze experimental measurements of vessel diameter and blood pressure obtained in vitro at conditions mimicking in vivo dynamics. Elastic and viscoelastic wall properties were assessed via solutions to the associated inverse problem. We use sensitivity analysis to rank the model parameters from the most to the least sensitive, as well as to compute standard errors and confidence intervals. Results reveal that elastic properties in both models (including Youngs modulus and the viscoelastic relaxation parameters) vary across locations (smaller arteries are stiffer than larger arteries). We also show that for all locations, the inclusion of viscoelastic behavior is important to capture pressure-area dynamics.

Linear and Nonlinear Viscoelastic Modeling of Aorta and Carotid Pressure–Area Dynamics Under In Vivo and Ex Vivo Conditions

A better understanding of the biomechanical properties of the arterial wall provides important insight into arterial vascular biology under normal (healthy) and pathological conditions. This insight has potential to improve tracking of disease progression and to aid in vascular graft design and implementation. In this study, we use linear and nonlinear viscoelastic models to predict biomechanical properties of the thoracic descending aorta and the carotid artery under ex vivo and in vivo conditions in ovine and human arteries. Models analyzed include a four-parameter (linear) Kelvin viscoelastic model and two five-parameter nonlinear viscoelastic models (an arctangent and a sigmoid model) that relate changes in arterial blood pressure to the vessel cross-sectional area (via estimation of vessel strain). These models were developed using the framework of Quasilinear Viscoelasticity (QLV) theory and were validated using measurements from the thoracic descending aorta and the carotid artery obtained from human and ovine arteries. In vivo measurements were obtained from 10 ovine aortas and 10 human carotid arteries. Ex vivo measurements (from both locations) were made in 11 male Merino sheep. Biomechanical properties were obtained through constrained estimation of model parameters. To further investigate the parameter estimates, we computed standard errors and confidence intervals and we used analysis of variance to compare results within and between groups. Overall, our results indicate that optimal model selection depends on the artery type. Results showed that for the thoracic descending aorta (under both experimental conditions), the best predictions were obtained with the nonlinear sigmoid model, while under healthy physiological pressure loading the carotid arteries nonlinear stiffening with increasing pressure is negligible, and consequently, the linear (Kelvin) viscoelastic model better describes the pressure–area dynamics in this vessel. Results comparing biomechanical properties show that the Kelvin and sigmoid models were able to predict the zero-pressure vessel radius; that under ex vivo conditions vessels are more rigid, and comparatively, that the carotid artery is stiffer than the thoracic descending aorta; and that the viscoelastic gain and relaxation parameters do not differ significantly between vessels or experimental conditions. In conclusion, our study demonstrates that the proposed models can predict pressure–area dynamics and that model parameters can be extracted for further interpretation of biomechanical properties.

Predicting Arterial Flow and Pressure Dynamics Using a 1D Fluid Dynamics Model with a Viscoelastic Wall

This paper combines a generalized viscoelastic model with a one-dimensional (1D) fluid dynamics model for the prediction of blood flow, pressure, and vessel area in systemic arteries. The 1D fluid dynamics model is derived from the Navier–Stokes equations for an incompressible Newtonian flow through a network of cylindrical vessels. This model predicts pressure and flow and is combined with a viscoelastic constitutive equation derived using the quasilinear viscoelasticity theory that relates pressure and vessel area. This formulation allows for inclusion of an elastic response as well as an appropriate creep function allowing for the description of the viscoelastic deformation of the arterial wall. Three constitutive models were investigated: a linear elastic model and two viscoelastic models. The Kelvin and sigmoidal viscoelastic models provide linear and nonlinear elastic responses, respectively. For the fluid domain, the model assumes that a given flow profile is prescribed at the inlet, that flow is c...

A murine experimental model for the mechanical behaviour of viable right-ventricular myocardium

•  Right‐ventricular (RV) function is an important determinant of cardio‐pulmonary performance. How and when RV failure occurs in disease is poorly understood. RV biomechanics provides a means to understand tissue level behavior that links cellular mechanisms to organ level phenotype. RV biomechanics has received little attention. •  We developed 1) rat model for quantifying the structure and biomechanical behavior of viable and transmurally intact RV tissue, and 2) a novel analysis method for obtaining representative scalar strain‐energy function from stress‐controlled biaxial experiments. •  The mechanical testing revealed a marked mechanical tissue anisotropy with the apex‐to‐outflow tract direction being the stiffer direction. •  The myo‐ and collagen fibers show a preferential alignment from the apex to the RV outflow tract direction with little transmural variation. •  We found a strong relationship between normal tissue microstructure and biomechanical behavior, which lays the foundation for a detailed understanding of RV remodeling in response to disease.

Nicotinamide Phosphoribosyltransferase Promotes Pulmonary Vascular Remodeling and is a Therapeutic Target in Pulmonary Arterial Hypertension

Background: Pulmonary arterial hypertension is a severe and progressive disease, a hallmark of which is pulmonary vascular remodeling. Nicotinamide phosphoribosyltransferase (NAMPT) is a cytozyme that regulates intracellular nicotinamide adenine dinucleotide levels and cellular redox state, regulates histone deacetylases, promotes cell proliferation, and inhibits apoptosis. We hypothesized that NAMPT promotes pulmonary vascular remodeling and that inhibition of NAMPT could attenuate pulmonary hypertension. Methods: Plasma, mRNA, and protein levels of NAMPT were measured in the lungs and isolated pulmonary artery endothelial cells from patients with pulmonary arterial hypertension and in the lungs of rodent models of pulmonary hypertension. Nampt+/− mice were exposed to 10% hypoxia and room air for 4 weeks, and the preventive and therapeutic effects of NAMPT inhibition were tested in the monocrotaline and Sugen hypoxia models of pulmonary hypertension. The effects of NAMPT activity on proliferation, migration, apoptosis, and calcium signaling were tested in human pulmonary artery smooth muscle cells. Results: Plasma and mRNA and protein levels of NAMPT were increased in the lungs and isolated pulmonary artery endothelial cells from patients with pulmonary arterial hypertension, as well as in lungs of rodent models of pulmonary hypertension. Nampt+/− mice were protected from hypoxia-mediated pulmonary hypertension. NAMPT activity promoted human pulmonary artery smooth muscle cell proliferation via a paracrine effect. In addition, recombinant NAMPT stimulated human pulmonary artery smooth muscle cell proliferation via enhancement of store-operated calcium entry by enhancing expression of Orai2 and STIM2. Last, inhibition of NAMPT activity attenuated monocrotaline and Sugen hypoxia–induced pulmonary hypertension in rats. Conclusions: Our data provide evidence that NAMPT plays a role in pulmonary vascular remodeling and that its inhibition could be a potential therapeutic target for pulmonary arterial hypertension.

Biaxial Properties of the Left and Right Pulmonary Arteries in a Monocrotaline Rat Animal Model of Pulmonary Arterial Hypertension

In a monocrotaline (MCT) induced-pulmonary arterial hypertension (PAH) rat animal model, the dynamic stress-strain relation was investigated in the circumferential and axial directions using a linear elastic response model within the quasi-linear viscoelasticity theory framework. Right and left pulmonary arterial segments (RPA and LPA) were mechanically tested in a tubular biaxial device at the early stage (1 week post-MCT treatment) and at the advanced stage of the disease (4 weeks post-MCT treatment). The vessels were tested circumferentially at the in vivo axial length with matching in vivo measured pressure ranges. Subsequently, the vessels were tested axially at the mean pulmonary arterial pressure by stretching them from in vivo plus 5% of their length. Parameter estimation showed that the LPA and RPA remodel at different rates: axially, both vessels decreased in Youngs modulus at the early stage of the disease, and increased at the advanced disease stage. Circumferentially, the Youngs modulus increased in advanced PAH, but it was only significant in the RPA. The damping properties also changed in PAH; in the LPA relaxation times decreased continuously as the disease progressed, while in the RPA they initially increased and then decreased. Our modeling efforts were corroborated by the restructuring organization of the fibers imaged under multiphoton microscopy, where the collagen fibers become strongly aligned to the 45 deg angle in the RPA from an uncrimped and randomly organized state. Additionally, collagen content increased almost 10% in the RPA from the placebo to advanced PAH.

Linear and nonlinear viscoelastic modeling of ovine aortic biomechanical properties under in vivo and ex vivo conditions

This study uses linear and nonlinear viscoelastic models to describe the dynamic distention of the aorta induced by time-varying arterial blood pressure. We employ an inverse mathematical modeling approach on a four-parameter (linear) Kelvin viscoelastic model and two five-parameter nonlinear viscoelastic models (arctangent and sigmoid) to infer vascular biomechanical properties under in vivo and ex vivo experimental conditions in ten and eleven male Merino sheep, respectively. We used the Akaike Information Criterion (AIC) as a goodness-of-fit measure. Results show that under both experimental conditions, the nonlinear models generally outperform the linear Kelvin model, as judged by the AIC. Furthermore, the sigmoid nonlinear viscoelastic model consistently achieves the lowest AIC and also matches the zero-stress vessel radii measured ex vivo. Based on these observations, we conclude that the sigmoid nonlinear viscoelastic model best describes the biomechanical properties of ovine large arteries under both experimental conditions considered in this study.

Modeling Viscoelastic Wall Properties of Ovine Arteries

Generation of a complete map of arterial wall mechanical properties can improve treatment of cardiovascular diseases via contributions to design of patient specific vascular substitutes used to alleviate atherosclerosis and stenoses, which are predominant in arterial pathways (i.e., abdominal aorta, carotids, or femoral arteries). Clinically useful estimation of arterial properties from patient data requires both efficient algorithms and models that are both complex enough to capture clinically important properties and simple enough to allow rapid computation. In this study, we used mechanical models accounting for both elastic and viscoelastic wall deformation to analyze how vessel properties and associated model parameters vary with artery type. It is known that for the aorta wall, deformation is dominated by nonlinear elastic dynamics, while for the smaller vessels (e.g. the carotid artery) deformation is dominated by viscoelastic responses. The latter is correlated with composition of the vessels; the aorta contains significantly less smooth muscle cells (∼40%) than the carotid artery (∼60%), and has significantly more elastin (see Fig 1).Copyright

Compensated right ventricular function of the onset of pulmonary hypertension in a rat model depends on chamber remodeling and contractile augmentation

Right-ventricular function is a good indicator of pulmonary arterial hypertension (PAH) prognosis; however, how the right ventricle (RV) adapts to the pressure overload is not well understood. Here, we aimed at characterizing the time course of RV early remodeling and discriminate the contribution of ventricular geometric remodeling and intrinsic changes in myocardial mechanical properties in a monocrotaline (MCT) animal model. In a longitudinal study of PAH, ventricular morphology and function were assessed weekly during the first four weeks after MCT exposure. Using invasive measurements of RV pressure and volume, heart performance was evaluated at end of systole and diastole to quantify contractility (end-systolic elastance) and chamber stiffness (end-diastolic elastance). To distinguish between morphological and intrinsic mechanisms, a computational model of the RV was developed and used to determine the level of prediction when accounting for wall masses and unloaded volume measurements changes. By four weeks, mean pulmonary arterial pressure and elastance rose significantly. RV pressures rose significantly after the second week accompanied by significant RV hypertrophy, but RV stroke volume and cardiac output were maintained. The model analysis suggested that, after two weeks, this compensation was only possible due to a significant increase in the intrinsic inotropy of RV myocardium. We conclude that this MCT-PAH rat is a model of RV compensation during the first month after treatment, where geometric remodeling on EDPVR and increased myocardial contractility on ESPVR are the major mechanisms by which stroke volume is preserved in the setting of elevated pulmonary arterial pressure. The mediators of this compensation might themselves promote longer-term adverse remodeling and decompensation in this animal model.

Lumped‐parameter models of the pulmonary vasculature during the progression of pulmonary arterial hypertension

A longitudinal study of monocrotaline‐induced pulmonary arterial hypertension (PAH) was carried out in Sprague‐Dawley rats to investigate the changes in impedance (comprising resistance and compliance) produced by elevated blood pressure. Using invasively measured blood flow as an input, blood pressure was predicted using 3‐ and 4‐element Windkessel (3WK, 4WK) type lumped‐parameter models. Resistance, compliance, and inductance model parameters were obtained for the five different treatment groups via least‐squares errors. The treated animals reached levels of hypertension, where blood pressure increased two folds from control to chronic stage of PAH (mean pressure went from 24 ± 5 to 44 ± 6 mmHg, P < 0.0001) but blood flow remained overall unaffected. Like blood pressure, the wave‐reflection coefficient significantly increased at the advanced stage of PAH (0.26 ± 0.09 to 0.52 ± 0.09, P < 0.0002). Our modeling efforts revealed that resistances and compliance changed during the disease progression, where changes in compliance occur before the changes in resistance. However, resistance and compliance are not directly inversely related. As PAH develops, resistances increase nonlinearly (Rd exponentially and R at a slower rate) while compliance linearly decreases. And while 3WK and 4WK models capture the pressure‐flow relation in the pulmonary vasculature during PAH, results from Akaike Information Criterion and sensitivity analysis allow us to conclude that the 3WK is the most robust and accurate model for this system. Ninety‐five percent confidence intervals of the predicted model parameters are included for the population studied. This work establishes insight into the complex remodeling process occurring in PAH.