Advances in computational modelling for personalised medicine after myocardial infarction

Myocardial infarction (MI) is a leading cause of premature morbidity and mortality worldwide. Determining which patients will experience heart failure and sudden cardiac death after an acute MI is notoriously difficult for clinicians. The extent of heart damage after an acute MI is informed by cardiac imaging, typically using echocardiography or sometimes, cardiac magnetic resonance (CMR). These scans provide complex data sets that are only partially exploited by clinicians in daily practice, implying potential for improved risk assessment. Computational modelling of left ventricular (LV) function can bridge the gap towards personalised medicine using cardiac imaging in patients with post-MI. Several novel biomechanical parameters have theoretical prognostic value and may be useful to reflect the biomechanical effects of novel preventive therapy for adverse remodelling post-MI. These parameters include myocardial contractility (regional and global), stiffness and stress. Further, the parameters can be delineated spatially to correspond with infarct pathology and the remote zone. While these parameters hold promise, there are challenges for translating MI modelling into clinical practice, including model uncertainty, validation and verification, as well as time-efficient processing. More research is needed to (1) simplify imaging with CMR in patients with post-MI, while preserving diagnostic accuracy and patient tolerance (2) to assess and validate novel biomechanical parameters against established prognostic biomarkers, such as LV ejection fraction and infarct size. Accessible software packages with minimal user interaction are also needed. Translating benefits to patients will be achieved through a multidisciplinary approach including clinicians, mathematicians, statisticians and industry partners

Estimating prognosis in patients with acute myocardial infarction using personalized computational heart models

Biomechanical computational models have potential prognostic utility in patients after an acute ST-segment–elevation myocardial infarction (STEMI). In a proof-of-concept study, we defined two groups (1) an acute STEMI group (n = 6, 83% male, age 54 ± 12 years) complicated by left ventricular (LV) systolic dysfunction; (2) an age- and sex- matched hyper-control group (n = 6, 83% male, age 46 ± 14 years), no prior history of cardiovascular disease and normal systolic blood pressure (SBP < 130 mmHg). Cardiac MRI was performed in the patients (2 days & 6 months post-STEMI) and the volunteers, and biomechanical heart models were synthesized for each subject. The candidate parameters included normalized active tension (ATnorm) and active tension at the resting sarcomere length (Treq, reflecting required contractility). Myocardial contractility was inversely determined from personalized heart models by matching CMR-imaged LV dynamics. Compared with controls, patients with recent STEMI exhibited increased LV wall active tension when normalized by SBP. We observed a linear relationship between Treq 2 days post-MI and global longitudinal strain 6 months later (r = 0.86; p = 0.03). Treq may be associated with changes in LV function in the longer term in STEMI patients complicated by LV dysfunction. Further studies seem warranted

Dynamic finite-strain modelling of the human left ventricle in health and disease using an immersed boundary-finite element method

Detailed models of the biomechanics of the heart are important both for developing improved interventions for patients with heart disease and also for patient risk stratification and treatment planning. For instance, stress distributions in the heart affect cardiac remodelling, but such distributions are not presently accessible in patients. Biomechanical models of the heart offer detailed three-dimensional deformation, stress and strain fields that can supplement conventional clinical data. In this work, we introduce dynamic computational models of the human left ventricle (LV) that are derived from clinical imaging data obtained from a healthy subject and from a patient with a myocardial infarction (MI). Both models incorporate a detailed invariant-based orthotropic description of the passive elasticity of the ventricular myocardium along with a detailed biophysical model of active tension generation in the ventricular muscle. These constitutive models are employed within a dynamic simulation framework that accounts for the inertia of the ventricular muscle and the blood that is based on an immersed boundary (IB) method with a finite element description of the structural mechanics. The geometry of the models is based on data obtained non-invasively by cardiac magnetic resonance (CMR). CMR imaging data are also used to estimate the parameters of the passive and active constitutive models, which are determined so that the simulated end-diastolic and end-systolic volumes agree with the corresponding volumes determined from the CMR imaging studies. Using these models, we simulate LV dynamics from end-diastole to end-systole. The results of our simulations are shown to be in good agreement with subject-specific CMR-derived strain measurements and also with earlier clinical studies on human LV strain distributions

Changes and classification in myocardial contractile function in the left ventricle following acute myocardial infarction

In this research, we hypothesized that novel biomechanical parameters are discriminative in patients following acute ST-segment elevation myocardial infarction (STEMI). To identify these biomechanical biomarkers and bring computational biomechanics ‘closer to the clinic’, we applied state-of-the-art multiphysics cardiac modelling combined with advanced machine learning and multivariate statistical inference to a clinical database of myocardial infarction. We obtained data from 11 STEMI patients (ClinicalTrials.gov NCT01717573) and 27 healthy volunteers, and developed personalized mathematical models for the left ventricle (LV) using an immersed boundary method. Subject-specific constitutive parameters were achieved by matching to clinical measurements. We have shown, for the first time, that compared with healthy controls, patients with STEMI exhibited increased LV wall active tension when normalized by systolic blood pressure, which suggests an increased demand on the contractile reserve of remote functional myocardium. The statistical analysis reveals that the required patient-specific contractility, normalized active tension and the systolic myofilament kinematics have the strongest explanatory power for identifying the myocardial function changes post-MI. We further observed a strong correlation between two biomarkers and the changes in LV ejection fraction at six months from baseline (the required contractility (r = − 0.79, p < 0.01) and the systolic myofilament kinematics (r = 0.70, p = 0.02)). The clinical and prognostic significance of these biomechanical parameters merits further scrutinization

Computational biomechanics of acute myocardial infarction and its treatment

The intramyocardial injection of biomaterials is an emerging therapy for myocardial infarction. Computational methods can help to study the mechanical effect s of biomaterial injectates on the infarcted heart s and can contribute to advance and optimise the concept of this therapy. The distribution of polyethylene glycol hydrogel injectate delivered immediately after the infarct induction was studied using rat infarct model. A micro-structural three-dimensional geometrical model of the entire injectate was reconstructed from histological micro graphs. The model provides a realistic representation of biomaterial injectates in computational models at macroscopic and microscopic level. Biaxial and compression mechanical testing was conducted for healing rat myocardial infarcted tissue at immediate (0 day), 7, 14 and 28 days after infarction onset. Infarcts were found to be mechanically anisotropic with the tissue being stiffer in circumferential direction than in longitudinal direction. The 0, 7, 14 and 28 days infarcts showed 443, 670, 857 and 1218 kPa circumferential tensile moduli. The 28 day infarct group showed a significantly higher compressive modulus compared to the other infarct groups (p= 0.0055, 0.028, and 0.018 for 0, 7 and 14 days groups). The biaxial mechanical data were utilized to establish material constitutive models of rat healing infarcts. Finite element model s and genetic algorithms were employed to identify the parameters of Fung orthotropic hyperelastic strain energy function for the healing infarcts. The provided infarct mechanical data and the identified constitutive parameters offer a platform for investigations of mechanical aspects of myocardial infarction and therapies in the rat, an experimental model extensively used in the development of infarct therapies. Micro-structurally detailed finite element model of a hydrogel injectate in an infarct was developed to provide an insight into the micromechanics of a hydrogel injectate and infarct during the diastolic filling. The injectate caused the end-diastolic fibre stresses in the infarct zone to decrease from 22.1 to 7.7 kPa in the 7 day infarct and from 35.7 to 9.7 kPa in the 28 day infarct. This stress reduction effect declined as the stiffness of the biomaterial increased. It is suggested that the gel works as a force attenuating system through micromechanical mechanisms reducing the force acting on tissue layers during the passive diastolic dilation of the left ventricle and thus reducing the stress induced in these tissue layers

Computational Investigation of Injectable Treatment Strategies for Myocardial Infarction

Heart failure is an important medical disease and impacts millions of people throughout the world. In order to treat this problem, biomaterial injectable treatment injected into the myocardium of the failing LV are currently being developed. Through this treatment, the biomaterial material injections can reduce wall stresses during the cardiac remodeling process. By using computational techniques to analyze the effects of a treatment involving the injection of biomaterial material into the LV after MI, the material parameters of the hydrogel injections can be optimized. The results shows that the hydrogel injections could reduce the global average fiber stress and the transmural average stress seen from optimization. These results indicated that the hydrogel injections could influence the stiffness in passive LV tissue, but there is still need for more research on the active part of ventricular contraction. Conclusion: hydrogel injection is a viable way to alter ventricular mechanical properties

Investigating left ventricular infarct extension after myocardial infarction using cardiac imaging and patient-specific modelling

Acute myocardial infarction (MI) is one of the leading causes of death worldwide that commonly affects the left ventricle (LV). Following MI, the LV mechanical loading is altered and may undergo a maladaptive compensatory mechanism that progressively leads to adverse LV remodelling and then heart failure. One of the remodelling processes is the infarct extension which involves necrosis of healthy myocardium in the border zone (BZ), progressively enlarging the infarct zone (IZ) and recruiting the remote zone (RZ) into the BZ. The mechanisms underlying infarct extension remain unclear, but myocyte stretching has been suggested as the most likely cause. A recent personalized LV modelling work found that infarct extension was correlated to inadequate diastolic fibre stretch and higher infarct stiffness. However, other possible factors of infarct extension may not have been elucidated in this work due to the limited number of myocardial locations analysed at the subendocardium only. Using human patient-specific left- ventricular (LV) models established from cardiac magnetic resonance imaging (MRI) of 6 MI patients, the correlation between infarct extension and regional mechanics impairment was studied. Prior to the modelling, a 2D-4D registration-cum-segmentation framework for the delineation of LV in late gadolinium enhanced (LGE) MRI was first developed, which is a pre-requisite for infarct scar quantification and localization in patient-specific 3D LV models. This framework automatically corrects for motion artifacts in multimodal MRI scans, resolving the issue of inaccurate infarct mapping and geometry reconstruction which is typically done manually in most patient-specific modelling work. The registration framework was evaluated against cardiac MRI data from 27 MI patients and showed high accuracy and robustness in delineating LV in LGE MRI of various quality and different myocardial features. This framework allows the integration of LV data from both LGE and cine scans and to facilitate the reconstruction of accurate 3D LV and infarct geometries for subsequent computational study. In the patient-specific LV mechanical modelling, the LV mechanics were formulated using a quasi-static and nearly incompressible hyperelastic material law with transversely isotropic behaviour. The patient-specific models were incorporated with realistic fibre orientation and excitable contracting myocardium. Optimisation of passive and active material parameters were done by minimizing the myocardial wall distance between the reference and end-diastole/end-systole LV geometries. Full cardiac cycle of the LV models was then simulated and stress/strain data were extracted to determine the correlation between regional mechanics abnormality and infarct extension. The fibre stress-strain loops (FSSLs) were analysed and its abnormality was characterized using the directional regional external work (DREW) index, which measures FSSL area and loop direction. Sensitivity studies were also performed to investigate the effect of infarct stiffness on regional myocardial mechanics and potential for infarct extension. It was found that infarct extension was correlated to severely abnormal FSSL in the form of counter-clockwise loop, as indicated by negative DREW values. In regions demonstrating negative DREW values, substantial isovolumic relaxation (IVR) fibre stretching was observed. Further analysis revealed that the occurrence of severely abnormal FSSL near the RZ-BZ boundary was due to a large amount of surrounding infarcted tissue that worsen with excessively stiff IZ

A Novel Composite Material-based Computational Model for Left Ventricle Biomechanics Simulation

To model cardiac mechanics effectively, various mechanical characteristics of cardiac muscle tissue including anisotropy, hyperelasticity, and tissue active contraction characteristics must be considered. Some of these features cannot be implemented using commercial finite element (FE) solvers unless additional custom-developed computer codes/subroutines are appended. Such codes/subroutines are unavailable for the research community. Accordingly, the overarching objective of this research is to develop a novel LV mechanics model which is implementable in commercial FE solvers and can be used effectively within inverse FE frameworks towards cardiac disease diagnosis and therapy. This was broken down into a number of objectives. The first objective is to develop a novel cardiac tissue mechanical model. This model was constructed of microstructural cardiac tissue constituents while their associated volume contributions and mechanical properties were incorporated into the model. These constituents were organized in small FE tissue specimen models consistent with the normal/pathological cardiac tissue microstructure. In silico biaxial/uniaxial mechanical tests were conducted on the specimen models and corresponding stress-strain data were validated by comparing them with cardiac tissue data reported in the literature. Another objective of this research is developing a novel FE-based mechanical model of the LV which is fully implementable using commercial FE solvers without requiring further coding, potentially leading to a computationally efficient model which is easily adaptable to diverse pathological conditions. This was achieved through considering a novel composite material model of the cardiac tissue while all aspects of the cardiac mechanics including hyperelasticity, anisotropy, and active tissue responses were preserved. The model was applied to an in silico geometry of a canine LV under both normal and pathological conditions and systolic/diastolic responses of the model were compared with corresponding data of other LV mechanical models and LV contraction measurements. To test the suitability of the proposed cardiac model for FE inversion-based algorithms, the model was utilized for LV diastolic mechanical simulation to estimate the tissue stiffness and blood pressure using an ad-hoc optimization scheme. This led to reasonable tissue stiffness and blood pressure values falling within the range of LV measurements of healthy subjects, confirming the efficacy of this model for inversion-based diagnosis applications

A COMPUTATIONAL STUDY OF PATCH IMPLANTATION AND MITRAL VALVE MECHANICS

Myocardial infarction (i.e., a heart attack) is the most common heart disease in the United States. Mitral valve regurgitation, or the backflow of blood into the atrium from the left ventricle, is one of the complications associated with myocardial infarction. In this dissertation, a validated model of a sheep heart that has suffered myocardial infarction has been employed to study mitral valve regurgitation. The model was rebuilt with the knowledge of geometrical changes captured with MRI technique and is assigned with anisotropic, inhomogeneous, nearly incompressible and highly non-linear material properties. Patch augmentation was performed on its anterior leaflet, using a simplified approach, and its posterior leaflet, using a more realistic approach. In this finite element simulation, we virtually installed an elliptical patch within the central portion of the posterior leaflet. To the best of the author’s knowledge, this type of simulation has not been performed previously. In another simulation, the effect of patch within the anterior leaflet was simulated. The results from the two different surgical simulations show that patch implantation helps the free edges of the leaflets come close to one another, which leads to improved coaptation. Additionally, the changes in chordal force distributions are also reported. Finally, this study answers a few questions regarding mitral valve patch augmentation surgeries and emphasizes the importance of further investigations on the influence of patch positioning and material properties on key outcomes. The ultimate goal is to use the proposed techniques to assess human models that are patient-specific

COMPUTATIONAL INVESTIGATION OF TRANSMURAL DIFFERENCES IN LEFT VENTRICULAR CONTRACTILITY AND HYDROGEL INJECTION TREATMENT FOR MYOCARDIAL INFARCTION

Heart failure (HF) is one of the leading causes of death and impacts millions of people throughout the world. Recently, injectable hydrogels have been developed as a potential new therapy to treat myocardium infarction (MI). This dissertation is focused on two main topics: 1) to gain a better understanding the transmural contractility in the healthy left ventricle (LV) wall and 2) investigate the efficacy of the hydrogel injection treatment on LV wall stress and function. The results indicate that a non-uniform distribution of myocardial contractility in the LV wall provide a better representation of normal LV function. The other important study explored the influence altering the stiffness of the biomaterial hydrogel injections. These results show that a larger volume and higher stiffness injection reduce myofiber stress the most and maintaining the wall thickness during loading. The computational approach developed in this dissertation could be used in the future to evaluate the optimal properties of the hydrogel. The last study used a combination of MRI, catheterization, finite element (FE) modeling to investigate the effects of hydrogel injection on borderzone (BZ) contractility after MI. The results indicate that the treatment with hydrogel injection significantly improved BZ function and reduce LV remodeling, via altered MI properties. Additionally, the wall thickness in the infarct and BZ regions were significantly higher in the treated case. Conclusion: hydrogel injection could be a valuable clinical therapy for treating MI