Comparing physiological impacts of positive pressure ventilation versus self-breathing via a versatile cardiopulmonary model incorporating a novel alveoli opening mechanism.

Mathematical models can be used to generate high-fidelity simulations of the cardiopulmonary system. Such models, when applied to real patients, can provide valuable insights into underlying physiological processes that are hard for clinicians to observe directly. In this work, we propose a novel modelling strategy capable of generating scenario-specific cardiopulmonary simulations to replicate the vital physiological signals clinicians use to determine the state of a patient. This model is composed of a tree-like pulmonary system that features a novel, non-linear alveoli opening strategy, based on the dynamics of balloon inflation, that interacts with the cardiovascular system via the thorax. A baseline simulation of the model is performed to measure the response of the system during spontaneous breathing which is subsequently compared to the same system under mechanical ventilation. To test the new lung opening mechanics and systematic recruitment of alveolar units, a positive end-expiratory pressure (PEEP) test is performed and its results are then compared to simulations of a deep spontaneous breath. The system displays a marked decrease in tidal volume as PEEP increases, replicating a sigmoidal curve relationship between volume and pressure. At high PEEP, cardiovascular function is shown to be visibly impaired, in contrast to the deep breath test where normal function is maintained.

Aneurysmal growth in type-B aortic dissection: assessing the impact of patient-specific inlet conditions on key haemodynamic indices.

Type-B aortic dissection is a cardiovascular disease in which a tear develops in the intimal layer of the descending aorta, allowing pressurized blood to delaminate the layers of the vessel wall. In medically managed patients, long-term aneurysmal dilatation of the false lumen (FL) is considered virtually inevitable and is associated with poorer disease outcomes. While the pathophysiological mechanisms driving FL dilatation are not yet understood, haemodynamic factors are believed to play a key role. Computational fluid dynamics (CFD) and 4D-flow MRI (4DMR) analyses have revealed correlations between flow helicity, oscillatory wall shear stress and aneurysmal dilatation of the FL. In this study, we compare CFD simulations using a patient-specific, three-dimensional, three-component inlet velocity profile (4D IVP) extracted from 4DMR data against simulations with flow rate-matched uniform and axial velocity profiles that remain widely used in the absence of 4DMR. We also evaluate the influence of measurement errors in 4DMR data by scaling the 4D IVP to the degree of imaging error detected in prior studies. We observe that oscillatory shear and helicity are highly sensitive to inlet velocity distribution and flow volume throughout the FL and conclude that the choice of IVP may greatly affect the future clinical value of simulations.

The Influence of Minor Aortic Branches in Patient-Specific Flow Simulations of Type-B Aortic Dissection.

Type-B aortic dissection (TBAD) is a disease in which a tear develops in the intimal layer of the descending aorta forming a true lumen and false lumen (FL). Because disease outcomes are thought to be influenced by haemodynamic quantities such as pressure and wall shear stress (WSS), their analysis via numerical simulations may provide valuable clinical insights. Major aortic branches are routinely included in simulations but minor branches are virtually always neglected, despite being implicated in TBAD progression and the development of complications. As minor branches are estimated to carry about 7-21% of cardiac output, neglecting them may affect simulation accuracy. We present the first simulation of TBAD with all pairs of intercostal, subcostal and lumbar arteries, using 4D-flow MRI (4DMR) to inform patient-specific boundary conditions. Compared to an equivalent case without minor branches, their inclusion improved agreement with 4DMR velocities, reduced time-averaged WSS (TAWSS) and transmural pressure and elevated oscillatory shear in regions where FL dilatation and calcification were observed in vivo. Minor branch inclusion resulted in differences of 60-75% in these metrics of potential clinical relevance, indicating a need to account for minor branch flow loss if simulation accuracy is sought.

Highly integrated workflows for exploring cardiovascular conditions: Exemplars of precision medicine in Alzheimer's disease and aortic dissection.

For precision medicine to be implemented through the lens of in silico technology, it is imperative that biophysical research workflows offer insight into treatments that are specific to a particular illness and to a particular subject. The boundaries of precision medicine can be extended using multiscale, biophysics-centred workflows that consider the fundamental underpinnings of the constituents of cells and tissues and their dynamic environments. Utilising numerical techniques that can capture the broad spectrum of biological flows within complex, deformable and permeable organs and tissues is of paramount importance when considering the core prerequisites of any state-of-the-art precision medicine pipeline. In this work, a succinct breakdown of two precision medicine pipelines developed within two Virtual Physiological Human (VPH) projects are given. The first workflow is targeted on the trajectory of Alzheimer's Disease, and caters for novel hypothesis testing through a multicompartmental poroelastic model which is integrated with a high throughput imaging workflow and subject-specific blood flow variability model. The second workflow gives rise to the patient specific exploration of Aortic Dissections via a multi-scale and compliant model, harnessing imaging, computational fluid-dynamics (CFD) and dynamic boundary conditions. Results relating to the first workflow include some core outputs of the multiporoelastic modelling framework, and the representation of peri-arterial swelling and peri-venous drainage solution fields. The latter solution fields were statistically analysed for a cohort of thirty-five subjects (stratified with respect to disease status, gender and activity level). The second workflow allowed for a better understanding of complex aortic dissection cases utilising both a rigid-wall model informed by minimal and clinically common datasets as well as a moving-wall model informed by rich datasets.

Using a Systems Pharmacology Approach to Study the Effect of Statins on the Early Stage of Atherosclerosis in Humans.

More than 100,000 people have participated in controlled trials of statins (lowering cholesterol drugs) since the introduction of lovastatin in the 1980s. Meta-analyses of this data have shown that statins have a beneficial effect on treated groups compared to control groups, reducing cardiovascular risk. Inhibiting the HMG-CoA reductase in the liver, statins can reduce cholesterol levels, thus reducing LDL levels in circulation. Published data from intravascular ultrasound studies (IVUS) was used in this work to develop and validate a unique integrative system model; this consisted of analyzing control groups from two randomized controlled statins trials (24/97 subjects respectively), one treated group (40 subjects, simvastatin trial), and 27 male subjects (simvastatin, pharmacokinetic study). The model allows to simulate the pharmacokinetics of statins and its effect on the dynamics of lipoproteins (e.g., LDL) and the inflammatory pathway while simultaneously exploring the effect of flow-related variables (e.g., wall shear stress) on atherosclerosis progression.

Fluid-structure interaction study of the edge-to-edge repair technique on the mitral valve.

The effect of functional mitral regurgitation has been investigated in an anatomically sized, fluid-structure interaction mitral valve model, where simulated correction has been performed by applying: (1) edge-to-edge repair with annuloplasty and (2) edge-to-edge repair only. Initially defined in an open unstressed/corrected configuration, fluid-structure interaction simulations of diastole have been performed in a rigid ventricular volume. Comparison of the maximum principal stresses (during diastole) in the normal and repaired models has shown that the magnitude of stress in the repaired scenarios is ~200% greater. The combined edge-to-edge and annuloplasty procedure was found to spread the induced stresses across the free margin of the leaflets, whereas without annuloplasty a localised stress concentration in the region of the suture was observed. Fluid flow downstream of the corrected configurations was able to achieve the same magnitude as in the normal case, although the flow rate was impaired. The maximum flow rate was found to be reduced by 44-50% with the peak flow rate shifted from the end of the diastole in the normal case to the start in the repaired cases.

Adaptation and development of software simulation methodologies for cardiovascular engineering: present and future challenges from an end-user perspective.

This paper describes the use of diverse software tools in cardiovascular applications. These tools were primarily developed in the field of engineering and the applications presented push the boundaries of the software to address events related to venous and arterial valve closure, exploration of dynamic boundary conditions or the inclusion of multi-scale boundary conditions from protein to organ levels. The future of cardiovascular research and the challenges that modellers and clinicians face from validation to clinical uptake are discussed from an end-user perspective.