Using LDDMM and a kinematic cardiac growth model to quantify growth and remodelling in rat hearts under PAH.

Pulmonary arterial hypertension (PAH) is a rapidly progressive and fatal disease, with right ventricular failure being the primary cause of death in patients with PAH. This study aims to determine the mechanical stimuli that may initiate heart growth and remodelling (G&R). To achieve this, two bi-ventricular models were constructed: one for a control rat heart and another for a rat heart with PAH. The growth of the diseased heart was estimated by warping it to the control heart using an improved large deformation diffeomorphic metric mapping (LDDMM) framework. Correlation analysis was then performed between mechanical cues (stress and strain) and growth tensors, which revealed that principal strains may serve as a triggering stimulus for myocardial growth and remodelling under PAH. The growth tensors, estimated from in vivo images, could explain 84.3% of the observed geometrical changes in the diseased heart with PAH by using a kinematic cardiac growth model. Our approach has the potential to quantify G&R using sparse in vivo images and to provide insights into the underlying mechanism of triggering right heart failure from a biomechanical perspective.

An updated Lagrangian constrained mixture model of pathological cardiac growth and remodelling.

Progressive left ventricular (LV) growth and remodelling (G&R) is often induced by volume and pressure overload, characterized by structural and functional adaptation through myocyte hypertrophy and extracellular matrix remodelling, which are dynamically regulated by biomechanical factors, inflammation, neurohormonal pathways, etc. When prolonged, it can eventually lead to irreversible heart failure. In this study, we have developed a new framework for modelling pathological cardiac G&R based on constrained mixture theory using an updated reference configuration, which is triggered by altered biomechanical factors to restore biomechanical homeostasis. Eccentric and concentric growth, and their combination have been explored in a patient-specific human LV model under volume and pressure overload. Eccentric growth is triggered by overstretching of myofibres due to volume overload, i.e. mitral regurgitation, whilst concentric growth is driven by excessive contractile stress due to pressure overload, i.e. aortic stenosis. Different biological constituent's adaptations under pathological conditions are integrated together, which are the ground matrix, myofibres and collagen network. We have shown that this constrained mixture-motivated G&R model can capture different phenotypes of maladaptive LV G&R, such as chamber dilation and wall thinning under volume overload, wall thickening under pressure overload, and more complex patterns under both pressure and volume overload. We have further demonstrated how collagen G&R would affect LV structural and functional adaption by providing mechanistic insight on anti-fibrotic interventions. This updated Lagrangian constrained mixture based myocardial G&R model has the potential to understand the turnover processes of myocytes and collagen due to altered local mechanical stimuli in heart diseases, and in providing mechanistic links between biomechanical factors and biological adaption at both the organ and cellular levels. Once calibrated with patient data, it can be used for assessing heart failure risk and designing optimal treatment therapies. STATEMENT OF SIGNIFICANCE: Computational modelling of cardiac G&R has shown high promise to provide insight into heart disease management when mechanistic understandings are quantified between biomechanical factors and underlying cellular adaptation processes. The kinematic growth theory has been dominantly used to phenomenologically describe the biological G&R process but neglecting underlying cellular mechanisms. We have developed a constrained mixture based G&R model with updated reference by taking into account different mechanobiological processes in the ground matrix, myocytes and collagen fibres. This G&R model can serve as a basis for developing more advanced myocardial G&R models further informed by patient data to assess heart failure risk, predict disease progression, select the optimal treatment by hypothesis testing, and eventually towards a truly precision cardiology using in-silico models.

Association of cerebral infarction with vertebral arterial fenestration using non-Newtonian hemodynamic evaluation.

PURPOSE: Cerebral artery fenestration is a rare vascular anomaly, but its existence has been increasingly documented. The association of cerebral infarction and fenestration is of great clinical interest, and the exact underlying mechanism remains unclear. This study aims to identify risk factors contributing to cerebral infarction by computational hemodynamics analysis. METHODS: Eight patients with image findings of fenestration structure were recruited in this research, in which four suffered fenestration-related cerebral infarction (A series) while the other four (B series) were set as control matched by the fenestration size. Three-dimensional models were reconstructed from the MRA images and computational simulations with non-Newtonian flow model were performed to get interested hemodynamic characteristics. RESULTS: The blood flow pattern was relatively separated along two channels of fenestration in series A compared with series B cases in Group 1-2, however, no significant difference was shown in Group 3-4. Quantitatively, planes were cut in the middle of fenestrations and the ratio of mass flow rate and area was calculated at systolic peak. Results showed that the side of the dominant blood supply was opposite between A and B series, and the dominant side was also opposite between small and large fenestrations. In infarction cases, the basilar top was distributed with larger areas of detrimental hemodynamic indicators and a larger concentrated high viscosity region. CONCLUSION: The flow division condition throughout the fenestration structure has a key impact on further flow redistribution and flow pattern. The blood viscosity has the potential to be a useful tool in identifying the risk factors for cerebral infarction and more emphasis should be placed on the hemodynamic environment at superior cerebellar arteries.

A new active contraction model for the myocardium using a modified hill model.

This study develops a new hybrid active contraction model for myocardial dynamics abstracted from sarcomere by combining the phenomenologically active-stress based Hill model and the micro-structurally motivated active strain approach. This new model consists of a passive branch and a parallel active branch that consists of a serial passive element for active tension transmission and a contractile unit for active tension development. This rheology represents an additive decomposition of the total stress into a passive and active response. The active stress is formulated following the active strain approach based on the sliding filament theory by multiplicatively decomposing the stretch of the contractile element into a fictitious and an active part. The length-dependence and force-velocity are further incorporated in the active strain. We estimate the passive stiffness of the serial passive element using literature data, which is 250 kPa, then the active stress is computed from the serial passive element in the active branch because of its force transmission structure. This one-dimensional contraction model is further generalized to three dimensions for modelling myocardial dynamics. Our results demonstrate that the proposed active contraction model has a high descriptive capability for various experiments, including both isometric and isotonic contraction compared to existing active strain approaches. We also show that it can simulate physiologically accurate cardiac dynamics in humans. The excellent agreement with experimental data and a local sensitivity study highlight the importance of length-dependence and force-velocity in the active strain approach. Our results further show that there exists a tight interaction between the length-dependence and force-velocity relationships. This new hybrid model serves as a step forward in personalized cardiac modelling using an active-strain based contraction model and has the potential to understand the multi-scale coupling in active contraction according to the sliding filament theory.

Effects of dispersed fibres in myocardial mechanics, Part I: passive response.

It is widely acknowledged that an imbalanced biomechanical environment can have significant effects on myocardial pathology, leading to adverse remodelling of cardiac function if it persists. Accurate stress prediction essentially depends on the strain energy function which should have competent descriptive and predictive capabilities. Previous studies have focused on myofibre dispersion, but not on fibres along other directions. In this study, we will investigate how fibre dispersion affects myocardial biomechanical behaviours by taking into account both the myofibre dispersion and the sheet fibre dispersion, with a focus on the sheet fibre dispersion. Fibre dispersion is incorporated into a widely-used myocardial strain energy function using the discrete fibre bundle approach. We first study how different dispersion affects the descriptive capability of the strain energy function when fitting to ex vivo experimental data, and then the predictive capability in a human left ventricle during diastole. Our results show that the chosen strain energy function can achieve the best goodness-of-fit to the experimental data by including both fibre dispersion. Furthermore, noticeable differences in stress can be found in the LV model. Our results may suggest that it is necessary to include both dispersion for myofibres and the sheet fibres for the improved descriptive capability to the ex vivo experimental data and potentially more accurate stress prediction in cardiac mechanics.

Effects of dispersed fibres in myocardial mechanics, Part II: active response.

This work accompanies the first part of our study "effects of dispersed fibres in myocardial mechanics: Part I passive response" with a focus on myocardial active contraction. Existing studies have suggested that myofibre architecture plays an important role in myocardial active contraction. Following the first part of our study, we firstly study how the general fibre architecture affects ventricular pump function by varying the mean myofibre rotation angles, and then the impact of fibre dispersion along the myofibre direction on myocardial contraction in a left ventricle model. Dispersed active stress is described by a generalised structure tensor method for its computational efficiency. Our results show that both the myofibre rotation angle and its dispersion can significantly affect cardiac pump function by redistributing active tension circumferentially and longitudinally. For example, larger myofibre rotation angle and higher active tension along the sheet-normal direction can lead to much reduced end-systolic volume and higher longitudinal shortening, and thus a larger ejection fraction. In summary, these two studies together have demonstrated that it is necessary and essential to include realistic fibre structures (both fibre rotation angle and fibre dispersion) in personalised cardiac modelling for accurate myocardial dynamics prediction.

Effect of myofibre architecture on ventricular pump function by using a neonatal porcine heart model: from DT-MRI to rule-based methods.

Myofibre architecture is one of the essential components when constructing personalized cardiac models. In this study, we develop a neonatal porcine bi-ventricle model with three different myofibre architectures for the left ventricle (LV). The most realistic one is derived from ex vivo diffusion tensor magnetic resonance imaging, and other two simplifications are based on rule-based methods (RBM): one is regionally dependent by dividing the LV into 17 segments, each with different myofibre angles, and the other is more simplified by assigning a set of myofibre angles across the whole ventricle. Results from different myofibre architectures are compared in terms of cardiac pump function. We show that the model with the most realistic myofibre architecture can produce larger cardiac output, higher ejection fraction and larger apical twist compared with those of the rule-based models under the same pre/after-loads. Our results also reveal that when the cross-fibre contraction is included, the active stress seems to play a dual role: its sheet-normal component enhances the ventricular contraction while its sheet component does the opposite. We further show that by including non-symmetric fibre dispersion using a general structural tensor, even the most simplified rule-based myofibre model can achieve similar pump function as the most realistic one, and cross-fibre contraction components can be determined from this non-symmetric dispersion approach. Thus, our study highlights the importance of including myofibre dispersion in cardiac modelling if RBM are used, especially in personalized models.

On the AIC-based model reduction for the general Holzapfel-Ogden myocardial constitutive law.

Constitutive laws that describe the mechanical responses of cardiac tissue under loading hold the key to accurately model the biomechanical behaviour of the heart. There have been ample choices of phenomenological constitutive laws derived from experiments, some of which are quite sophisticated and include effects of microscopic fibre structures of the myocardium. A typical example is the strain-invariant-based Holzapfel-Ogden 2009 model that is excellently fitted to simple shear tests. It has been widely used and regarded as the state-of-the-art constitutive law for myocardium. However, there has been no analysis to show if it has both adequate descriptive and predictive capabilities for other tissue tests of myocardium. Indeed, such an analysis is important for any constitutive laws for clinically useful computational simulations. In this work, we perform such an analysis using combinations of tissue tests, uniaxial tension, biaxial tension and simple shear from three different sets of myocardial tissue studies. Starting from the general 14-parameter myocardial constitutive law developed by Holzapfel and Ogden, denoted as the general HO model, we show that this model has good descriptive and predictive capabilities for all the experimental tests. However, to reliably determine all 14 parameters of the model from experiments remains a great challenge. Our aim is to reduce the constitutive law using Akaike information criterion, to maintain its mechanical integrity whilst achieving minimal computational cost. A competent constitutive law should have descriptive and predictive capabilities for different tissue tests. By competent, we mean the model has least terms but is still able to describe and predict experimental data. We also investigate the optimal combinations of tissue tests for a given constitutive model. For example, our results show that using one of the reduced HO models, one may need just one shear response (along normal-fibre direction) and one biaxial stretch (ratio of 1 mean fibre : 1 cross-fibre) to satisfactorily describe Sommer et al. human myocardial mechanical properties. Our study suggests that single-state tests (i.e. simple shear or stretching only) are insufficient to determine the myocardium responses. We also found it is important to consider transmural fibre rotations within each myocardial sample of tests during the fitting process. This is done by excluding un-stretched fibres using an "effective fibre ratio", which depends on the sample size, shape, local myofibre architecture and loading conditions. We conclude that a competent myocardium material model can be obtained from the general HO model using AIC analysis and a suitable combination of tissue tests.

Determinant Factors for Arterial Hemodynamics in Hypertension: Theoretical Insights From a Computational Model-Based Study.

Hypertension is a well-documented predictive factor for cardiovascular events. Clinical studies have extensively demonstrated the differential hemodynamic consequences of various antihypertensive drugs, but failed to clearly elucidate the underlying mechanisms due to the difficulty in performing a quantitative deterministic analysis based on clinical data that carry confounding information stemming from interpatient differences and the nonlinearity of cardiovascular hemodynamics. In the present study, a multiscale model of the cardiovascular system was developed to quantitatively investigate the relationships between hemodynamic variables and cardiovascular properties under hypertensive conditions, aiming to establish a theoretical basis for assisting in the interpretation of clinical observations or optimization of therapy. Results demonstrated that heart period, central arterial stiffness, and arteriolar radius were the major determinant factors for blood pressures and flow pulsatility indices both in large arteries and in the microcirculation. These factors differed in the degree and the way in which they affect hemodynamic variables due to their differential effects on wave reflections in the vascular system. In particular, it was found that the hemodynamic effects of varying arteriolar radius were considerably influenced by the state of central arterial stiffness, and vice versa, which implied the potential of optimizing antihypertensive treatment by selecting proper drugs based on patient-specific cardiovascular conditions. When analyzed in relation to clinical observations, the simulated results provided mechanistic explanations for the beneficial pressure-lowering effects of vasodilators as compared to ß-blockers, and highlighted the significance of monitoring and normalizing arterial stiffness in the treatment of hypertension.

Comparison of the Windkessel model and structured-tree model applied to prescribe outflow boundary conditions for a one-dimensional arterial tree model.

One-dimensional (1D) modeling is a widely adopted approach for studying wave propagation phenomena in the arterial system. Despite the frequent use of the Windkessel (WK) model to prescribe outflow boundary conditions for 1D arterial tree models, it remains unclear to what extent the inherent limitation of the WK model in describing wave propagation in distal vasculatures affect hemodynamic variables simulated at the arterial level. In the present study, a 1D model of the arterial tree was coupled respectively with a WK boundary model and a structured-tree (ST) boundary model, yielding two types of arterial tree models. The effective resistances, compliances and inductances of the WK and ST boundary models were matched to facilitate quantitative comparisons. Obtained results showed that pressure/flow waves simulated by the two models were comparable in the aorta, whereas, their discrepancies increased towards the periphery. Wave analysis revealed that the differences in reflected waves generated by the boundary models were the major sources of pressure wave discrepancies observed in large arteries. Additional simulations performed under aging conditions demonstrated that arterial stiffening with age enlarged the discrepancies, but with the effects being partly counteracted by physiological aortic dilatation with age. These findings suggest that the method adopted for modeling the outflow boundary conditions has considerable influence on the performance of a 1D arterial tree model, with the extent of influence varying with the properties of the arterial system.