Steven Niederer

Verification of cardiac tissue electrophysiology simulators using an N-version benchmark

Ongoing developments in cardiac modelling have resulted, in particular, in the development of advanced and increasingly complex computational frameworks for simulating cardiac tissue electrophysiology. The goal of these simulations is often to represent the detailed physiology and pathologies of the heart using codes that exploit the computational potential of high-performance computing architectures. These developments have rapidly progressed the simulation capacity of cardiac virtual physiological human style models; however, they have also made it increasingly challenging to verify that a given code provides a faithful representation of the purported governing equations and corresponding solution techniques. This study provides the first cardiac tissue electrophysiology simulation benchmark to allow these codes to be verified. The benchmark was successfully evaluated on 11 simulation platforms to generate a consensus gold-standard converged solution. The benchmark definition in combination with the gold-standard solution can now be used to verify new simulation codes and numerical methods in the future.

Coupling multi-physics models to cardiac mechanics

We outline and review the mathematical framework for representing mechanical deformation and contraction of the cardiac ventricles, and how this behaviour integrates with other processes crucial for understanding and modelling heart function. Building on general conservation principles of space, mass and momentum, we introduce an arbitrary Eulerian-Lagrangian framework governing the behaviour of both fluid and solid components. Exploiting the natural alignment of cardiac mechanical properties with the tissue microstructure, finite deformation measures and myocardial constitutive relations are referred to embedded structural axes. Coupling approaches for solving this large deformation mechanics framework with three dimensional fluid flow, coronary hemodynamics and electrical activation are described. We also discuss the potential of cardiac mechanics modelling for clinical applications.

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.

Length-dependent tension in the failing heart and the efficacy of cardiac resynchronization therapy

AIMS Cardiac resynchronization therapy (CRT) has emerged as one of the few effective and safe treatments for heart failure. However, identifying patients that will benefit from CRT remains controversial. The dependence of CRT efficacy on organ and cellular scale mechanisms was investigated in a patient-specific computer model to identify novel patient selection criteria. METHODS AND RESULTS A biophysically based patient-specific coupled electromechanics heart model has been developed which links the cellular and sub-cellular mechanisms which regulate cardiac function to the whole organ function observed clinically before and after CRT. A sensitivity analysis of the model identified lack of length dependence of tension regulation within the sarcomere as a significant contributor to the efficacy of CRT. Further simulation analysis demonstrated that in the whole heart, length-dependent tension development is key not only for the beat-to-beat regulation of stroke volume (Frank-Starling mechanism), but also the homogenization of tension development and strain. CONCLUSIONS In individuals with effective Frank-Starling mechanism, the length dependence of tension facilitates the homogenization of stress and strain. This can result in synchronous contraction despite asynchronous electrical activation. In these individuals, synchronizing electrical activation through CRT may have minimal benefit.

A meta‐analysis of cardiac electrophysiology computational models

Computational models of cardiac electrophysiology are exemplar demonstrations of the integration of multiple data sets into a consistent biophysical framework. These models encapsulate physiological understanding to provide quantitative predictions of function. The combination or extension of existing models within a common framework allows integrative phenomena in larger systems to be investigated. This methodology is now routinely applied, as demonstrated by the increasing number of studies which use or extend previously developed models. In this study, we present a meta‐analysis of this model re‐use for two leading models of cardiac electrophysiology in the form of parameter inheritance trees, a sensitivity analysis and a comparison of the functional significance of the sodium potassium pump for defining restitution curves. These results indicate that even though the models aim to represent the same physiological system, both the sources of parameter values and the function of equivalent components are significantly different.

An accurate, fast and robust method to generate patient-specific cubic Hermite meshes.

In-silico continuum simulations of organ and tissue scale physiology often require a discretisation or mesh of the solution domain. Cubic Hermite meshes provide a smooth representation of anatomy that is well-suited for simulating large deformation mechanics. Models of organ mechanics and deformation have demonstrated significant potential for clinical application. However, the production of a personalised mesh from patients anatomy using medical images remains a major bottleneck in simulation workflows. To address this issue, we have developed an accurate, fast and automatic method for deriving patient-specific cubic Hermite meshes. The proposed solution customises a predefined template with a fast binary image registration step and a novel cubic Hermite mesh warping constructed using a variational technique. Image registration is used to retrieve the mapping field between the template mesh and the patient images. The variational warping technique then finds a smooth and accurate projection of this field into the basis functions of the mesh. Applying this methodology, cubic Hermite meshes are fitted to the binary description of shape with sub-voxel accuracy and within a few minutes, which is a significant advance over the existing state of the art methods. To demonstrate its clinical utility, a generic cubic Hermite heart biventricular model is personalised to the anatomy of four patients, and the resulting mechanical stability of these customised meshes is successfully demonstrated.

Simulating human cardiac electrophysiology on clinical time-scales.

In this study, the feasibility of conducting in silico experiments in near-realtime with anatomically realistic, biophysically detailed models of human cardiac electrophysiology is demonstrated using a current national high-performance computing facility. The required performance is achieved by integrating and optimizing load balancing and parallel I/O, which lead to strongly scalable simulations up to 16,384 compute cores. This degree of parallelization enables computer simulations of human cardiac electrophysiology at 240 times slower than real time and activation times can be simulated in approximately 1 min. This unprecedented speed suffices requirements for introducing in silico experimentation into a clinical workflow.

Biophysical Modeling to Simulate the Response to Multisite Left Ventricular Stimulation Using a Quadripolar Pacing Lead

Background:  Response to cardiac resynchronization therapy (CRT) is reduced in patients with posterolateral scar. Multipolar pacing leads offer the ability to select desirable pacing sites and/or stimulate from multiple pacing sites concurrently using a single lead position. Despite this potential, the clinical evaluation and identification of metrics for optimization of multisite CRT (MCRT) has not been performed.

The estimation of patient-specific cardiac diastolic functions from clinical measurements

An unresolved issue in patients with diastolic dysfunction is that the estimation of myocardial stiffness cannot be decoupled from diastolic residual active tension (AT) because of the impaired ventricular relaxation during diastole. To address this problem, this paper presents a method for estimating diastolic mechanical parameters of the left ventricle (LV) from cine and tagged MRI measurements and LV cavity pressure recordings, separating the passive myocardial constitutive properties and diastolic residual AT. Dynamic C1-continuous meshes are automatically built from the anatomy and deformation captured from dynamic MRI sequences. Diastolic deformation is simulated using a mechanical model that combines passive and active material properties. The problem of non-uniqueness of constitutive parameter estimation using the well known Guccione law is characterized by reformulation of this law. Using this reformulated form, and by constraining the constitutive parameters to be constant across time points during diastole, we separate the effects of passive constitutive properties and the residual AT during diastolic relaxation. Finally, the method is applied to two clinical cases and one control, demonstrating that increased residual AT during diastole provides a potential novel index for delineating healthy and pathological cases.

A comparison of left ventricular endocardial, multisite, and multipolar epicardial cardiac resynchronization: an acute haemodynamic and electroanatomical study

AIMS Alternative forms of cardiac resynchronization therapy (CRT), including biventricular endocardial (BV-Endo) and multisite epicardial pacing (MSP), have been developed to improve response. It is unclear which form of stimulation is optimal. We aimed to compare the acute haemodynamic response (AHR) and electrophysiological effects of BV-Endo with MSP via two separate coronary sinus (CS) leads or a single-quadripolar CS lead. METHODS AND RESULTS Fifteen patients with a previously implanted CRT system received a second temporary CS lead and left ventricular (LV) endocardial catheter. A pressure wire and non-contact mapping array were placed into the LV cavity to measure LVdP/dtmax and perform electroanatomical mapping. Conventional CRT, BV-Endo, and MSP were then performed (MSP-1 via two epicardial leads and MSP-2 via a single-quadripolar lead). The best overall AHR was found using BV-Endo pacing with a 19.6 ± 13.6% increase in AHR at the optimal endocardial site over baseline (P < 0.001). There was an increase in LVdP/dtmax with MSP-1 and MSP-2 compared with conventional CRT, but this was not statistically significant. Biventricular endocardial pacing from the optimal site was significantly superior to conventional CRT (P = 0.039). The AHR achieved when BV-Endo pacing was highly site specific. Within individuals, the best pacing modality varied and was affected by the underlying substrate. Left ventricular activation times did not predict the optimal haemodynamic configuration. CONCLUSION Biventricular endocardial pacing and not MSP was superior to conventional CRT, but was highly site specific. Within individuals, however, different methods of stimulation are optimal and may need to be tailored to the underlying substrate.