Translational Research: Multi-Scale Models of the Pulmonary Circulation in Health and Disease - Multiscale Computer Modeling in Biomechanics and Biomedical Engineering - page 276

at rest and in non-exercise conditions (e.g. fidgeting or walking) [ 99 ] to estimate
the level of activity required to induce hypertension in nine subject-specific
geometries representing patients clinically presenting with PE. They found that
hypertension could be predicted in patients whose cardiac output was consistent
with upright fidgeting (so only low levels of activity or stress) in the absence of
any active response to embolization. This study paved the way for the first truly
subject specific modeling of pulmonary function in disease. Each of (1) anatomical
geometry (lungs, lobes, airways and blood vessels), (2) height-, weight- and age-
dependent metabolic rates, and (3) individualized embolus location and sizes were
incorporated into the model. The patients enrolled in the study were chosen so as
to avoid the confounding factor of existing lung disease, and model predictions
correlated well to both accepted population norms for parameters such as PVR and
PaO 2 in baseline conditions, and actual patient response. Of the patients included
in the study, those with predicted global hypoxia (P aO2 \ 80 mmHg) all had RV
dysfunction in the clinical setting, and all the patients without predicted global
hypoxia did not have RV dysfunction. Hypoxia, and/or the hypercapnia that
commonly accompanies it, is known to elevate cardiac output and ventilatory rate
[ 100 ] and this response may be crucial in understanding the variable outcomes in
PE. Multiscale modeling of the pulmonary circulation has therefore suggested that
oxygen (and carbon dioxide) transport may be crucial in understanding this
pathology of the pulmonary circulation. This opens the arena for a new class of
multi-scale models of the pulmonary circulation in future studies that are able to
relate cell or vessel levels response to stress or oxygen tensions and emergent
function at the organ level.
6 Linking to Cellular Mechanics
Although current models for the pulmonary circulation have achieved a high level
of sophistication in their structure and coupling of scale-dependent function, they
are currently lacking representation of important dynamic behaviors. For example,
the arteries and veins are treated as passive structures that distend and recoil in
response to transmural pressure only: they do not include force development in the
vascular smooth muscle (VSM). Further, the studies of Burrowes et al. [ 22 , 25 , 26 ,
28 - 30 , 33 , 34 ] and Clark et al. [ 17 , 31 , 32 ] assumed fully developed steady-state
flow to compute the distribution of blood, but not its spatio-temporal fluctuations.
Multi-scale model development for the airway tree and its interaction with the
parenchyma provides a roadmap for how vascular smooth muscle could be inte-
grated with models for the pulmonary circulation [ 101 ].
Politi et al. [ 101 ] presented a multi-scale model for force development in airway
smooth muscle (ASM) and its interaction with phasic force fluctuations at the airway,
tissue, and organ level (illustrated in Fig. 8 ). The model includes molecular-scale
phenomena, i.e. attachment of actin and myosin that is regulated by calcium (Ca 2+ )
dependent mechanisms, via a four-state model for the smooth muscle cross-bridge