Computational modeling reveals inflammation-driven dilatation of the pulmonary autograft in aortic position

Biomechanics and Modeling in Mechanobiology - The pulmonary autograft in the Ross procedure, where the aortic valve is replaced by the patient’s own pulmonary valve, is prone to failure due...     

Computational modeling of RBC and neutrophil transit through the pulmonary capillaries.

A computational model of the pulmonary microcirculation is developed and used to examine blood flow from arteriole to venule through a realistically complex alveolar capillary bed. Distributions of flow, hematocrit, and pressure are presented, showing the existence of preferential pathways through the system and of large segment-to-segment differences in all parameters, confirming and extending previous work. Red blood cell (RBC) and neutrophil transit are also analyzed, the latter drawing from previous studies of leukocyte aspiration into micropipettes. Transit time distributions are in good agreement with in vivo experiments, in particular showing that neutrophils are dramatically slowed relative to the flow of RBCs because of the need to contract and elongate to fit through narrower capillaries. Predicted neutrophil transit times depend on how the effective capillary diameter is defined. Transient blockage by a neutrophil can increase the local pressure drop across a segment by 100--300%, leading to temporal variations in flow and pressure as seen by videomicroscopy. All of these effects are modulated by changes in transpulmonary pressure and arteriolar pressure, although RBCs, neutrophils, and rigid microspheres all behave differently.     

Computational modeling of left heart diastolic function: examination of ventricular dysfunction

A computational model that accounts for blood-tissue interaction under physiological flow conditions was developed and applied to a thin-walled model of the left heart. This model consisted of the left ventricle, left atrium, and pulmonary vein flow. The input functions for the model included the pulmonary vein driving pressure and time-dependent relationship for changes in chamber tissue properties during the simulation. The Immersed Boundary Method was used for the interaction of the tissue and blood in response to fluid forces and changes in tissue pathophysiology, and the fluid mass and momentum conservation equations were solved using Patankar's Semi-Implicit Method for Pressure Linked Equations (SIMPLE). This model was used to examine the flow fields in the left heart under abnormal diastolic conditions of delayed ventricular relaxation, delayed ventricular relaxation with increased ventricular stiffness, and delayed ventricular relaxation with an increased atrial contraction. The results obtained from the left heart model were compared to clinically observed diastolic flow conditions, and to the results from simulations of normal diastolic function in this model [1]. Cases involving impairment of diastolic function were modeled with changes to the input functions for fiber relaxation/contraction of the chambers. The three cases of diastolic dysfunction investigated agreed with the changes in diastolic flow fields seen clinically. The effect of delayed relaxation was to decrease the early filling magnitude, and this decrease was larger when the stiffness of the ventricle was increased. Also, increasing the contraction of the atrium during atrial systole resulted in a higher late filling velocity and atrial pressure. The results show that dysfunction can be modeled by changing the relationships for fiber resting-length and/or stiffness. This provides confidence in future modeling of disease, especially changes to chamber properties to examine the effect of local dysfunction on global flow fields.     

Computational modeling of cardiac growth in the post-natal rat with a strain-based growth law

IntroductionThe postnatal heart grows mostly in response to increased hemodynamic load. However, the specific biomechanical stimuli that stimulate cardiac growth as a reaction to increased hemodynamic load are still poorly understood. It has been shown that isolated neonatal rat cardiac myocytes normalize resting sarcomere length by adding sarcomeres in series when subjected to uniaxial static strain. Because there is experimental evidence that myocytes can distinguish the direction of stretch, it was postulated that myocytes also may normalize interfilament lattice spacing as a response to cross-fiber stretch.MethodsA growth law was proposed in which fiber axial growth was stimulated by fiber strain deviating from zero and fiber radial growth by cross-fiber strain (parallel to the wall surface) deviating from zero. Fiber radial growth rate constant was 1/3 of the fiber axial growth rate constant. The growth law was implemented in a finite element model of the newborn Sprague-Dawley rat residually stressed left ventricle (LV). The LV was subjected to an end-diastolic pressure of 1 kPa and about 25 weeks of normal growth was simulated.ResultsMost cellular and chamber dimension changes in the model matched experimentally measured ones: LV cavity and wall volume increased from 2.3 and 54 μl, respectively, in the newborn to 276 μl and 1.1 ml, respectively, in the adult rat; LV shape became more spherical; internal LV radius increased faster than wall thickness; and unloaded sarcomere lengths exhibited a transmural gradient. The major discrepancy with experiments included a reversed transmural gradient of cell length in the older rat.ConclusionA novel strain-based growth law has been presented that reproduced physiological postnatal growth in the rat LV.     

Computational modeling of volumetric soft tissue growth: application to the cardiac left ventricle

As an initial step to investigate stimulus–response relations in growth and remodeling (G&R) of cardiac tissue, this study aims to develop a method to simulate 3D-inhomogeneous volumetric growth. Growth is regarded as a deformation that is decomposed into a plastic component which describes unconstrained growth and an elastic component to satisfy continuity of the tissue after growth. In current growth models, a single reference configuration is used that remains fixed throughout the entire growth process. However, considering continuous turnover to occur together with growth, such a fixed reference is unlikely to exist in reality. Therefore, we investigated the effect of tissue turnover on growth by incrementally updating the reference configuration. With both a fixed reference and an updated reference, strain-induced cardiac growth in magnitude of 30% could be simulated. However, with an updated reference, the amplitude of the stimulus for growth decreased over time, whereas with a fixed reference this amplitude increased. We conclude that, when modeling volumetric growth, the choice of the reference configuration is of great importance for the computed growth.     

Bosentan in pulmonary arterial hypertension: a comparison between congenital heart disease and chronic pulmonary embolism

Background. In patients with pulmonary hypertension, it is unknown whether the treatment effect of bosentan is dependent on the duration of pulmonary vessel changes. Therefore, we studied the response to bosentan in patients with life-long pulmonary vessel changes (pulmonary arterial hypertension (PAH) due to congenital heart disease (CHD)) and in patients with subacutely induced pulmonary vessel changes (chronic thromboembolic pulmonary hypertension (CTEPH)). Methods. In this open-label study, 18 patients with PAH due to CHD and 16 patients with CTEPH were treated with bosentan for at least one year. All patients were evaluated at baseline and during follow-up by means of the six-minute walk distance (6-MWD) and laboratory tests. Results. Improvement of 6-MWD was comparable in patients with PAH due to CHD (444±112 m to 471±100 m, p=0.02), and in CTEPH (376±152 m to 423±141 m, p=0.03) after three months of treatment. After this improvement, 6-MWD stabilised in both groups. Conclusion. Although duration of pulmonary vessel changes is strikingly different in patients with PAH due to CHD and CTEPH, the effect of one year of bosentan treatment was comparable. The main treatment effect appears to be disease stabilisation and decreasing the rate of deterioration. (Neth Heart J 2009;17:334–8.)     

Computational modeling reveals molecular details of epidermal growth factor binding

Background  

The ErbB family of receptors are dysregulated in a number of cancers, and the signaling pathway of this receptor family is a critical target for several anti-cancer drugs. Therefore a detailed understanding of the mechanisms of receptor activation is critical. However, despite a plethora of biochemical studies and recent single particle tracking experiments, the early molecular mechanisms involving epidermal growth factor (EGF) binding and EGF receptor (EGFR) dimerization are not as well understood. Herein, we describe a spatially distributed Monte Carlo based simulation framework to enable the simulation of in vivo receptor diffusion and dimerization.     

Comparative characteristics of systemic and pulmonary hemodynamics during changes in the heart preloading

A greater degree of relative shifts in the systemic arterial pressure in enhancing the right heart pre-load as compared with its diminishing. A primary role of the compensation mechanisms of the enhanced systemic arterial pressure level. The main role in the compensation of integral shifts of the arterial pressure induced by changes in the heart pre-load was shown to belong to the vascular resistance both in the major and the minor circulation circles. An idea of a greater involvement of the capacity function of the vascular bed in the minor circulation circle as compared with that in the major circulation circle in systemic haemodynamic shifts in changes of the heart pre-load, has been advanced.     

Computational modeling of dendrites

Computational methods have been part of neuroscience for many years. For example, models developed with these methods have provided a theory that helps explain the action potential. More recently, as experimental patch-electrode techniques have revealed new biophysics related to dendritic function and synaptic integration, computational models of dendrites have been developed to explain and further illuminate these results, and to predict possible additional behavior. Here, a collection of computational models of dendrites is reviewed. The goal is to help explain how such computational techniques work, some of their limitations, and what one can hope to learn about dendrites by modeling them.     

Disrupted pulmonary vascular development and pulmonary hypertension in transgenic mice overexpressing transforming growth factor-alpha

Pulmonary vascular disease plays a major role in morbidity and mortality in infant and adult lung diseases in which increased levels of transforming growth factor (TGF)-alpha and its receptor EGFR have been associated. The aim of this study was to determine whether overexpression of TGF-alpha disrupts pulmonary vascular development and causes pulmonary hypertension. Lung-specific expression of TGF-alpha in transgenic mice was driven with the human surfactant protein (SP)-C promoter. Pulmonary arteriograms and arterial counts show that pulmonary vascular development was severely disrupted in TGF-alpha mice. TGF-alpha mice developed severe pulmonary hypertension and vascular remodeling characterized by abnormally extensive muscularization of small pulmonary arteries. Pulmonary vascular development was significantly improved and pulmonary hypertension and vascular remodeling were prevented in bi-transgenic mice expressing both TGF-alpha and a dominant-negative mutant EGF receptor under the control of the SP-C promoter. Vascular endothelial growth factor (VEGF-A), an important angiogenic factor produced by the distal epithelium, was decreased in the lungs of TGF-alpha adults and in the lungs of infant TGF-alpha mice before detectable abnormalities in pulmonary vascular development. Hence, overexpression of TGF-alpha caused severe pulmonary vascular disease, which was mediated through EGFR signaling in distal epithelial cells. Reductions in VEGF may contribute to the pathogenesis of pulmonary vascular disease in TGF-alpha mice.