Effects of Electrical and Structural Remodeling on Atrial Fibrillation Maintenance: A Simulation Study

Atrial fibrillation, a common cardiac arrhythmia, often progresses unfavourably: in patients with long-term atrial fibrillation, fibrillatory episodes are typically of increased duration and frequency of occurrence relative to healthy controls. This is due to electrical, structural, and contractile remodeling processes. We investigated mechanisms of how electrical and structural remodeling contribute to perpetuation of simulated atrial fibrillation, using a mathematical model of the human atrial action potential incorporated into an anatomically realistic three-dimensional structural model of the human atria. Electrical and structural remodeling both shortened the atrial wavelength - electrical remodeling primarily through a decrease in action potential duration, while structural remodeling primarily slowed conduction. The decrease in wavelength correlates with an increase in the average duration of atrial fibrillation/flutter episodes. The dependence of reentry duration on wavelength was the same for electrical vs. structural remodeling. However, the dynamics during atrial reentry varied between electrical, structural, and combined electrical and structural remodeling in several ways, including: (i) with structural remodeling there were more occurrences of fragmented wavefronts and hence more filaments than during electrical remodeling; (ii) dominant waves anchored around different anatomical obstacles in electrical vs. structural remodeling; (iii) dominant waves were often not anchored in combined electrical and structural remodeling. We conclude that, in simulated atrial fibrillation, the wavelength dependence of reentry duration is similar for electrical and structural remodeling, despite major differences in overall dynamics, including maximal number of filaments, wave fragmentation, restitution properties, and whether dominant waves are anchored to anatomical obstacles or spiralling freely

Scroll-Wave Dynamics in Human Cardiac Tissue: Lessons from a Mathematical Model with Inhomogeneities and Fiber Architecture

Cardiac arrhythmias, such as ventricular tachycardia (VT) and ventricular fibrillation (VF), are among the leading causes of death in the industrialized world. These are associated with the formation of spiral and scroll waves of electrical activation in cardiac tissue; single spiral and scroll waves are believed to be associated with VT whereas their turbulent analogs are associated with VF. Thus, the study of these waves is an important biophysical problem. We present a systematic study of the combined effects of muscle-fiber rotation and inhomogeneities on scroll-wave dynamics in the TNNP (ten Tusscher Noble Noble Panfilov) model for human cardiac tissue. In particular, we use the three-dimensional TNNP model with fiber rotation and consider both conduction and ionic inhomogeneities. We find that, in addition to displaying a sensitive dependence on the positions, sizes, and types of inhomogeneities, scroll-wave dynamics also depends delicately upon the degree of fiber rotation. We find that the tendency of scroll waves to anchor to cylindrical conduction inhomogeneities increases with the radius of the inhomogeneity. Furthermore, the filament of the scroll wave can exhibit drift or meandering, transmural bending, twisting, and break-up. If the scroll-wave filament exhibits weak meandering, then there is a fine balance between the anchoring of this wave at the inhomogeneity and a disruption of wave-pinning by fiber rotation. If this filament displays strong meandering, then again the anchoring is suppressed by fiber rotation; also, the scroll wave can be eliminated from most of the layers only to be regenerated by a seed wave. Ionic inhomogeneities can also lead to an anchoring of the scroll wave; scroll waves can now enter the region inside an ionic inhomogeneity and can display a coexistence of spatiotemporal chaos and quasi-periodic behavior in different parts of the simulation domain. We discuss the experimental implications of our study

Mathematical Modeling and Simulation of Ventricular Activation Sequences: Implications for Cardiac Resynchronization Therapy

Next to clinical and experimental research, mathematical modeling plays a crucial role in medicine. Biomedical research takes place on many different levels, from molecules to the whole organism. Due to the complexity of biological systems, the interactions between components are often difficult or impossible to understand without the help of mathematical models. Mathematical models of cardiac electrophysiology have made a tremendous progress since the first numerical ECG simulations in the 1960s. This paper briefly reviews the development of this field and discusses some example cases where models have helped us forward, emphasizing applications that are relevant for the study of heart failure and cardiac resynchronization therapy

A component architecture for simulator development

Research, Development and Engineering applications require the rapid development of simulators, preferably through the reuse of simulator components. In order to facilitate the reuse and exchange of simulator components, research institutes and industry in The Netherlands are collaborating in the SIMULTAAN project. The main result of this project will be a simulator component architecture that facilitates ‘plug & play’ with components to build a simulator. Another result will be a component repository, which facilitates the exchange of simulator components. The realization of the simulator architecture is the Run-time Communication Infrastructure (RCI). The application programmer is shielded from the complexity of simulator interoperability standards. In addition to inter-federate communication, the RCI will also provide inter-component communication. If performance requirements are met, intercomponent communication will be based on an available HLA-RTI, otherwise a dedicated RTI will be developed

Adaptive Modeling of Ionic Membrane Currents Improves Models of Cardiac Electromechanics

Abstract A change in activation sequence by means of pacing induces changes in action potential (AP) morphology and duration. These changes are caused by electrical remodeling of ionic membrane currents and are reflected in the T wave in the electrocardiogram (ECG). Also the calcium transient is affected, which leads to changes in cardiomechanics. By modeling the cardiac muscle as a single fiber, we investigated whether electrical remodeling may be triggered by changes in mechanical load. A homogeneous distribution of electrophysiology in our model resulted in an inhomogeneous distribution of stroke work. After remodeling of the ionic membrane currents, contraction was more homogeneous and the repolarization wave was reversed. These results are in agreement with experimentally observed homogeneity in mechanics and heterogeneity in electrophysiology. In conclusion, adaptive modeling of electrophysiology may improve current models of cardiac electromechanics. Introduction Regional variation in action potential (AP) duration and morphology is related to regional differences in ionic membrane currents. Transmural heterogeneity in electrophysiology is related to differences in excitationcontraction coupling (ECC) and is believed to help synchronize contraction of the heart muscle [1]. In models of cardiac electromechanics, heterogeneity in electrophysiology and ECC should be incorporated to obtain a more homogeneous mechanical behavior as observed in experiments In 1982, Rosenbaum et al. [4] observed that longer lasting epicardial pacing leads to a change in the T wave of the ECG. With normal sinus rhythm, concordance of the T wave reappears after some time. Since it appears that the cardiac myocytes somehow "remember" their original state, this phenomenon is known as "cardiac memory" Recent experimental observations indicate that electrical remodeling is triggered by changes in mechanical load (mechanoelectric feedback) Methods Cardiac electrophysiology and mechanics is modeled by the Cellular Bidomain Model Cardiac electrophysiology The electrophysiological state of each segment is defined by the intracellular potential (V int ), the extracellular potential (V ext ), and the state of the cell membrane, which is expressed in gating variables and ion concentrations. The membrane potential (V mem ) is defined by V mem = V int − V ext . Exchange of current between the intracellular and extracellular domains occurs as transmembrane current (I trans ), which depends on ionic current (I ion ) and capacitive current according to where χ = 2000 cm −1 is the ratio of membrane area to tissue volume and C mem = 1.0 µF/cm 2 represents membrane capacitance per unit membrane surface. To model I ion , we apply the Courtemanche-RamirezNattel mode

Modeling cardiac electromechanics and mechanoelectrical coupling in dyssynchronous and failing hearts : insight from adaptive computer models

Computer models have become more and more a research tool to obtain mechanistic insight in the effects of dyssynchrony and heart failure. Increasing computational power in combination with increasing amounts of experimental and clinical data enables the development of mathematical models that describe electrical and mechanical behavior of the heart. By combining models based on data at the molecular and cellular level with models that describe organ function, so-called multi-scale models are created that describe heart function at different length and time scales. In this review, we describe basic modules that can be identified in multi-scale models of cardiac electromechanics. These modules simulate ionic membrane currents, calcium handling, excitation–contraction coupling, action potential propagation, and cardiac mechanics and hemodynamics. In addition, we discuss adaptive modeling approaches that aim to address long-term effects of diseases and therapy on growth, changes in fiber orientation, ionic membrane currents, and calcium handling. Finally, we discuss the first developments in patient-specific modeling. While current models still have shortcomings, well-chosen applications show promising results on some ultimate goals: understanding mechanisms of dyssynchronous heart failure and tuning pacing strategy to a particular patient, even before starting the therapy

A computational model of the retina

Although the retina is one of the best understood parts of the central nervous system, manymysteries of this complex tissue have not yet been unraveled. We have used computationalmodeling to comprise knowledge from literature and gain more knowledge in the interactionsbetween neurons on two levels. Here we present two models: the network model, which describesthe whole neuronal network of the retina and the ephaptic model, which deals with aspecific feedback mechanism between neurons (cones and horizontal cells) in the first layers ofthe retina.\u3cp\u3eIn the network model we have included all known information on the pathways involved in colorvision in the primate retina. The behavior and output of this model depends on the spatial,temporal as well as the spectral information of the visual input. The model contains 20 typesof neurons, representing 3 types of cones (photoreceptors), 2 types of horizontal cells, 8 types ofbipolar cells and 7 types of ganglion cells. For each type of neuron there is a layer with cells ofthat type placed on a hexagonal grid. Each individual neuron is described by differential equationsbased on an electrical network of a capacitor in parallel with a number of resistors. Someof these resistors represent synaptic connections, for which the resistance can be controlled byadjacent neurons in the same layer as well as neurons in other layers.\u3c/p\u3e\u3cp\u3eThe ephaptic model provides a more detailed description of the interaction between cones andhorizontal cells. For long it has been known that cone type photoreceptors convert light stimuliinto a chemical signal that is received by horizontal cells and bipolar cells. There is also a feedbacksignal from horizontal cells to cones. With our ephaptic model we study the hypothesisthat this feedback is caused by an ephaptic phenomenon, i.e., by the local modulation of extracellular ion concentrations. The differential equations describing the behavior of neurons in thismodel resemble those in the network model, but contain much more physiological detail, as wellas a description of the extra cellular potential in a specific region of the synapse.\u3c/p\u3e\u3cp\u3eSimulations with the network model show qualitative agreement with biological phenomena.Examples are differences in spatial resolution of the various pathways and the change in networkbehavior if one type of cone is missing (color blindness). However, the model lacks physiologicaldetail of the ephaptic interaction between cones and horizontal cells. This lack of physiologicaldetail can be filled in with our model of ephaptic feedback. The ephaptic model fits well withexperimental data and shows that ephaptic interaction can indeed explain feedback from horizontalcells to cones.\u3c/p\u3e\u3cp\u3eOur network model can be used to study the whole retina as if it were an image processingunit, whereas the ephaptic model can be used to study the specific interaction between conesand horizontal cells. The combination of the two models yields a model that can explain bothphysiological and perceptual phenomena.\u3c/p\u3

Mechanoelectric feedback leads to conduction slowing and block in acutely dilated atria : a modeling study of cardiac electromechanics

Atrial fibrillation is a common cardiac arrhythmia and is promoted by atrial dilatation. Acute atrial dilatation may play a role in atrial arrhythmogenesis through mechano-electric feedback. In experimental studies conduction slowing and block has been observedin acutely dilated atria. In the present study, the influence of the stretch-activated current Isac on impulse propagation is investigated by means of computer simulations. Both homogeneous and inhomogeneous atrial tissue are modeled by cardiac fibers composed of segments that are electrically andmechanically coupled. Active force is related to the concentration of free calcium ions as well as to the sarcomere length. Simulations of homogeneous and inhomogeneous cardiac fibers have been performed to quantify the relation between the conduction velocity and Isac under stretch. In our model, conduction slowing and block is related to the amount of stretch and is enhanced by contraction of early activated segments. Conduction block can be unidirectionalin an inhomogeneous fiber and is promoted by a shorter stimulation interval. Slowing of conduction is explained by inactivation of Ina channels and a lower maximum upstroke velocity (dVmem/dt)max due to a depolarized resting membrane potential. Conduction block at shorter stimulation intervals is explained by a longer effective refractory period under stretch.Our observations are in agreement with experimental results and explain the large differences in intra-atrial conduction as well as the increased inducibility of atrial fibrillation observed in acutely dilated atria