K. H. W. J. ten Tusscher

Cell model for efficient simulation of wave propagation in human ventricular tissue under normal and pathological conditions

In this paper, we formulate a model for human ventricular cells that is efficient enough for whole organ arrhythmia simulations yet detailed enough to capture the effects of cell level processes such as current blocks and channelopathies. The model is obtained from our detailed human ventricular cell model by using mathematical techniques to reduce the number of variables from 19 to nine. We carefully compare our full and reduced model at the single cell, cable and 2D tissue level and show that the reduced model has a very similar behaviour. Importantly, the new model correctly produces the effects of current blocks and channelopathies on AP and spiral wave behaviour, processes at the core of current day arrhythmia research. The new model is well over four times more efficient than the full model. We conclude that the new model can be used for efficient simulations of the effects of current changes on arrhythmias in the human heart.

Organization of ventricular fibrillation in the human heart: experiments and models.

Sudden cardiac death is a major health problem in the industrialized world. The lethal event is typically ventricular fibrillation (VF), during which the co‐ordinated regular contraction of the heart is overthrown by a state of mechanical and electrical anarchy. Understanding the excitation patterns that sustain VF is important in order to identify potential therapeutic targets. In this paper, we studied the organization of human VF by combining clinical recordings of electrical excitation patterns on the epicardial surface during in vivo human VF with simulations of VF in an anatomically and electrophysiologically detailed computational model of the human ventricles. We find both in the computational studies and in the clinical recordings that epicardial surface excitation patterns during VF contain around six rotors. Based on results from the simulated three‐dimensional excitation patterns during VF, which show that the total number of electrical sources is 1.4 ± 0.12 times greater than the number of epicardial rotors, we estimate that the total number of sources present during clinically recorded VF is 9.0 ± 2.6. This number is approximately fivefold fewer compared with that observed during VF in dog and pig hearts, which are of comparable size to human hearts. We explain this difference by considering differences in action potential duration dynamics across these species. The simpler spatial organization of human VF has important implications for treatment and prevention of this dangerous arrhythmia. Moreover, our findings underline the need for integrated research, in which human‐based clinical and computational studies complement animal research.

A computational study of mother rotor VF in the human ventricles

Sudden cardiac death is one of the major causes of death in the industrialized world. It is most often caused by a cardiac arrhythmia called ventricular fibrillation (VF). Despite its large social and economical impact, the mechanisms for VF in the human heart yet remain to be identified. Two of the most frequently discussed mechanisms observed in experiments with animal hearts are the multiple wavelet and mother rotor hypotheses. Most recordings of VF in animal hearts are consistent with the multiple wavelet mechanism. However, in animal hearts, mother rotor fibrillation has also been observed. For both multiple wavelet and mother rotor VF, cardiac heterogeneity plays an important role. Clinical data of action potential restitution measured from the surface of human hearts have been recently published. These in vivo data show a substantial degree of spatial heterogeneity. Using these clinical restitution data, we studied the dynamics of VF in the human heart using a heterogeneous computational model of human ventricles. We hypothesized that this observed heterogeneity can serve as a substrate for mother rotor fibrillation. We found that, based on these data, mother rotor VF can occur in the human heart and that ablation of the mother rotor terminates VF. Furthermore, we found that both mother rotor and multiple wavelet VF can occur in the same heart depending on the initial conditions at the onset of VF. We studied the organization of these two types of VF in terms of filament numbers, excitation periods, and frequency domains. We conclude that mother rotor fibrillation is a possible mechanism in the human heart.

Wave Propagation in Excitable Media with Randomly Distributed Obstacles

We study the effect of small, randomly distributed obstacles on wave propagation in two-dimensional (2D) and 3D excitable media described by the Aliev--Panfilov model. We find that increasing the number of obstacles decreases the conduction velocity of plane waves and decreases the effective diffusion coefficient in the eikonal curvature equation. The presence of obstacles also increases the inducibility of wave breaks and spiral waves in 2D and 3D excitable media, but suppresses spiral breakup induced by a steep restitution curve mechanism. We discuss the mechanisms of the observed effects, the differences between 2D and 3D excitable media, as well as the relevance of our study to processes of wave propagation in cardiac tissue, including arrhythmogenesis in the presence of fibrosis in the myocardium.

Mechanisms and constraints shaping the evolution of body plan segmentation

Abstract.Segmentation of the major body axis into repeating units is arguably one of the major inventions in the evolution of animal body plan pattering. It is found in current day vertebrates, annelids and arthropods. Most segmented animals seem to use a clock-and-wavefront type mechanism in which oscillations emanating from a posterior growth zone become transformed into an anterior posterior sequence of segments. In contrast, few animals such as Drosophila use a complex gene regulatory hierarchy to simultaneously subdivide their entire body axis into segments. Here I discuss how in silico models simulating the evolution of developmental patterning can be used to investigate the forces and constraints that helped shape these two developmental modes. I perform an analysis of a series of previous simulation studies, exploiting the similarities and differences in their outcomes in relation to model characteristics to elucidate the circumstances and constraints likely to have been important for the evolution of sequential and simultaneous segmentation modes. The analysis suggests that constraints arising from the involved growth process and spatial patterning signal --posterior elongation producing a propagating wavefront versus a tissue wide morphogen gradient-- and the evolutionary history --ancestral versus derived segmentation mode-- strongly shaped both segmentation mechanisms. Furthermore, this implies that these patterning types are to be expected rather than random evolutionary outcomes and supports the likelihood of multiple parallel evolutionary origins.Graphical abstract