Cardiac cell modelling: Observations from the heart of the cardiac physiome project

In this manuscript we review the state of cardiac cell modelling in the context of international initiatives such as the IUPS Physiome and Virtual Physiological Human Projects, which aim to integrate computational models across scales and physics. In particular we focus on the relationship between experimental data and model parameterisation across a range of model types and cellular physiological systems. Finally, in the context of parameter identification and model reuse within the Cardiac Physiome, we suggest some future priority areas for this field

Effects of Cardiac Structural Remodelling During Heart Failure on Cardiac Excitation – Insights from a Heterogeneous 3D Model of the Rabbit Atria

Heart failure is a leading cause of morbidity and mortality in the western world. One of the effects of heart failure is the structural remodelling of cardiac tissue, including tissue dilation and development of fibrosis. It is therefore important to study these changes and their effect on cardiac activity, in order to gain a better understanding of the underlying mechanisms in arrhythmogenesis, which will hopefully enable us to develop better treatments for heart failure. In this study we developed biophysically detailed models of the rabbit atria for normal and heart failure conditions. These models were used to study the effects of structural remodelling of heart failure on cardiac excitation wave conduction. Anatomical reconstructions of the control and heart failure hearts were based on contrast enhanced micro-CT imaging. Fibre orientation was extracted from the control and heart failure datasets. Effects of heart failure geometry on the activation pattern of atrial excitation waves were analyzed. It was found that atrial activation time increased from the control to the heart failure case in both isotropic and anisotropic conditions, which is attributed primarily to the dilation of tissue caused by heart failure

A new algorithm to diagnose atrial ectopic origin from multi lead ECG systems - insights from 3D virtual human atria and torso

Rapid atrial arrhythmias such as atrial fibrillation (AF) predispose to ventricular arrhythmias, sudden cardiac death and stroke. Identifying the origin of atrial ectopic activity from the electrocardiogram (ECG) can help to diagnose the early onset of AF in a cost-effective manner. The complex and rapid atrial electrical activity during AF makes it difficult to obtain detailed information on atrial activation using the standard 12-lead ECG alone. Compared to conventional 12-lead ECG, more detailed ECG lead configurations may provide further information about spatio-temporal dynamics of the body surface potential (BSP) during atrial excitation. We apply a recently developed 3D human atrial model to simulate electrical activity during normal sinus rhythm and ectopic pacing. The atrial model is placed into a newly developed torso model which considers the presence of the lungs, liver and spinal cord. A boundary element method is used to compute the BSP resulting from atrial excitation. Elements of the torso mesh corresponding to the locations of the placement of the electrodes in the standard 12-lead and a more detailed 64-lead ECG configuration were selected. The ectopic focal activity was simulated at various origins across all the different regions of the atria. Simulated BSP maps during normal atrial excitation (i.e. sinoatrial node excitation) were compared to those observed experimentally (obtained from the 64-lead ECG system), showing a strong agreement between the evolution in time of the simulated and experimental data in the P-wave morphology of the ECG and dipole evolution. An algorithm to obtain the location of the stimulus from a 64-lead ECG system was developed. The algorithm presented had a success rate of 93%, meaning that it correctly identified the origin of atrial focus in 75/80 simulations, and involved a general approach relevant to any multi-lead ECG system. This represents a significant improvement over previously developed algorithms

High resolution 3-Dimensional imaging of the human cardiac conduction system from microanatomy to mathematical modeling

Cardiac arrhythmias and conduction disturbances are accompanied by structural remodelling of the specialised cardiomyocytes known collectively as the cardiac conduction system. Here, using contrast enhanced micro-computed tomography, we present, in attitudinally appropriate fashion, the first 3-dimensional representations of the cardiac conduction system within the intact human heart. We show that cardiomyocyte orientation can be extracted from these datasets at spatial resolutions approaching the single cell. These data show that commonly accepted anatomical representations are oversimplified. We have incorporated the high-resolution anatomical data into mathematical simulations of cardiac electrical depolarisation. The data presented should have multidisciplinary impact. Since the rate of depolarisation is dictated by cardiac microstructure, and the precise orientation of the cardiomyocytes, our data should improve the fidelity of mathematical models. By showing the precise 3-dimensional relationships between the cardiac conduction system and surrounding structures, we provide new insights relevant to valvar replacement surgery and ablation therapies. We also offer a practical method for investigation of remodelling in disease, and thus, virtual pathology and archiving. Such data presented as 3D images or 3D printed models, will inform discussions between medical teams and their patients, and aid the education of medical and surgical trainees

Endogenous driving and synchronization in cardiac and uterine virtual tissues: bifurcations and local coupling

Cardiac and uterine muscle cells and tissue can be either autorhythmic or excitable. These behaviours exchange stability at bifurcations produced by changes in parameters, which if spatially localized can produce an ectopic pacemaking focus. The effects of these parameters on cell dynamics have been identified and quantified using continuation algorithms and by numerical solutions of virtual cells. The ability of a compact pacemaker to drive the surrounding excitable tissues depends on both the size of the pacemaker and the strength of electrotonic coupling between cells within, between, and outside the pacemaking region. We investigate an ectopic pacemaker surrounded by normal excitable tissue. Cell–cell coupling is simulated by the diffusion coefficient for voltage. For uniformly coupled tissues, the behaviour of the hybrid tissue can take one of the three forms: (i) the surrounding tissue electrotonically suppresses the pacemaker; (ii) depressed rate oscillatory activity in the pacemaker but no propagation; and (iii) pacemaker driving propagations into the excitable region. However, real tissues are heterogeneous with spatial changes in cell–cell coupling. In the gravid uterus during early pregnancy, cells are weakly coupled, with the cell–cell coupling increasing during late pregnancy, allowing synchronous contractions during labour. These effects are investigated for a caricature uterine tissue by allowing both excitability and diffusion coefficient to vary stochastically with space, and for cardiac tissues by spatial gradients in the diffusion coefficient

Simulation of action potential propagation based on the ghost structure method

In this paper, a ghost structure (GS) method is proposed to simulate the monodomain model in irregular computational domains using finite difference without regenerating body-fitted grids. In order to verify the validity of the GS method, it is first used to solve the Fitzhugh-Nagumo monodomain model in rectangular and circular regions at different states (the stationary and moving states). Then, the GS method is used to simulate the propagation of the action potential (AP) in transverse and longitudinal sections of a healthy human heart, and with left bundle branch block (LBBB). Finally, we analyze the AP and calcium concentration under healthy and LBBB conditions. Our numerical results show that the GS method can accurately simulate AP propagation with different computational domains either stationary or moving, and we also find that LBBB will cause the left ventricle to contract later than the right ventricle, which in turn affects synchronized contraction of the two ventricles

Analysis of Heterogeneous Cardiac Pacemaker Tissue Models and Traveling Wave Dynamics

The sinoatrial-node (SAN) is a complex heterogeneous tissue that generates a stable rhythm in healthy hearts, yet a general mechanistic explanation for when and how this tissue remains stable is lacking. Although computational and theoretical analyses could elucidate these phenomena, such methods have rarely been used in realistic (large-dimensional) gap-junction coupled heterogeneous pacemaker tissue models. In this study, we adapt a recent model of pacemaker cells (Severi et al. 2012), incorporating biophysical representations of ion channel and intracellular calcium dynamics, to capture physiological features of a heterogeneous population of pacemaker cells, in particular "center" and "peripheral" cells with distinct intrinsic frequencies and action potential morphology. Large-scale simulations of the SAN tissue, represented by a heterogeneous tissue structure of pacemaker cells, exhibit a rich repertoire of behaviors, including complete synchrony, traveling waves of activity originating from periphery to center, and transient traveling waves originating from the center. We use phase reduction methods that do not require fully simulating the large-scale model to capture these observations. Moreover, the phase reduced models accurately predict key properties of the tissue electrical dynamics, including wave frequencies when synchronization occurs, and wave propagation direction in a variety of tissue models. With the reduced phase models, we analyze the relationship between cell distributions and coupling strengths and the resulting transient dynamics. Further, the reduced phase model predicts parameter regimes of irregular electrical dynamics. Thus, we demonstrate that phase reduced oscillator models applied to realistic pacemaker tissue is a useful tool for investigating the spatial-temporal dynamics of cardiac pacemaker activity.Comment: 34 pages, 11 figure