297 research outputs found
Effect of Global Cardiac Ischemia on Human Ventricular Fibrillation: Insights from a Multi-scale Mechanistic Model of the Human Heart
Acute regional ischemia in the heart can lead to cardiac arrhythmias such as ventricular fibrillation (VF), which in turn compromise cardiac output and result in secondary global cardiac ischemia. The secondary ischemia may influence the underlying arrhythmia mechanism. A recent clinical study documents the effect of global cardiac ischaemia on the mechanisms of VF. During 150 seconds of global ischemia the dominant frequency of activation decreased, while after reperfusion it increased rapidly. At the same time the complexity of epicardial excitation, measured as the number of epicardical phase singularity points, remained approximately constant during ischemia. Here we perform numerical studies based on these clinical data and propose explanations for the observed dynamics of the period and complexity of activation patterns. In particular, we study the effects on ischemia in pseudo-1D and 2D cardiac tissue models as well as in an anatomically accurate model of human heart ventricles. We demonstrate that the fall of dominant frequency in VF during secondary ischemia can be explained by an increase in extracellular potassium, while the increase during reperfusion is consistent with washout of potassium and continued activation of the ATP-dependent potassium channels. We also suggest that memory effects are responsible for the observed complexity dynamics. In addition, we present unpublished clinical results of individual patient recordings and propose a way of estimating extracellular potassium and activation of ATP-dependent potassium channels from these measurements
Having Fun in Learning Formal Specifications
There are many benefits in providing formal specifications for our software.
However, teaching students to do this is not always easy as courses on formal
methods are often experienced as dry by students. This paper presents a game
called FormalZ that teachers can use to introduce some variation in their
class. Students can have some fun in playing the game and, while doing so, also
learn the basics of writing formal specifications in the form of pre- and
post-conditions. Unlike existing software engineering themed education games
such as Pex and Code Defenders, FormalZ takes the deep gamification approach
where playing gets a more central role in order to generate more engagement.
This short paper presents our work in progress: the first implementation of
FormalZ along with the result of a preliminary users' evaluation. This
implementation is functionally complete and tested, but the polishing of its
user interface is still future work
Selfsimilar solutions in a sector for a quasilinear parabolic equation
We study a two-point free boundary problem in a sector for a quasilinear
parabolic equation. The boundary conditions are assumed to be spatially and
temporally "self-similar" in a special way. We prove the existence, uniqueness
and asymptotic stability of an expanding solution which is self-similar at
discrete times. We also study the existence and uniqueness of a shrinking
solution which is self-similar at discrete times.Comment: 23 page
Incorporating Inductances in Tissue-Scale Models of Cardiac Electrophysiology
In standard models of cardiac electrophysiology, including the bidomain and
monodomain models, local perturbations can propagate at infinite speed. We
address this unrealistic property by developing a hyperbolic bidomain model
that is based on a generalization of Ohm's law with a Cattaneo-type model for
the fluxes. Further, we obtain a hyperbolic monodomain model in the case that
the intracellular and extracellular conductivity tensors have the same
anisotropy ratio. In one spatial dimension, the hyperbolic monodomain model is
equivalent to a cable model that includes axial inductances, and the relaxation
times of the Cattaneo fluxes are strictly related to these inductances. A
purely linear analysis shows that the inductances are negligible, but models of
cardiac electrophysiology are highly nonlinear, and linear predictions may not
capture the fully nonlinear dynamics. In fact, contrary to the linear analysis,
we show that for simple nonlinear ionic models, an increase in conduction
velocity is obtained for small and moderate values of the relaxation time. A
similar behavior is also demonstrated with biophysically detailed ionic models.
Using the Fenton-Karma model along with a low-order finite element spatial
discretization, we numerically analyze differences between the standard
monodomain model and the hyperbolic monodomain model. In a simple benchmark
test, we show that the propagation of the action potential is strongly
influenced by the alignment of the fibers with respect to the mesh in both the
parabolic and hyperbolic models when using relatively coarse spatial
discretizations. Accurate predictions of the conduction velocity require
computational mesh spacings on the order of a single cardiac cell. We also
compare the two formulations in the case of spiral break up and atrial
fibrillation in an anatomically detailed model of the left atrium, and [...].Comment: 20 pages, 12 figure
Arrhythmic risk biomarkers for the assessment of drug cardiotoxicity: from experiments to computer simulations
In this paper, we illustrate how advanced computational modelling and simulation can be used to investigate drug-induced effects on cardiac electrophysiology and on specific biomarkers of pro-arrhythmic risk. To do so, we first perform a thorough literature review of proposed arrhythmic risk biomarkers from the ionic to the electrocardiogram levels. The review highlights the variety of proposed biomarkers, the complexity of the mechanisms of drug-induced pro-arrhythmia and the existence of significant animal species differences in drug-induced effects on cardiac electrophysiology. Predicting drug-induced pro-arrhythmic risk solely using experiments is challenging both preclinically and clinically, as attested by the rise in the cost of releasing new compounds to the market. Computational modelling and simulation has significantly contributed to the understanding of cardiac electrophysiology and arrhythmias over the last 40 years. In the second part of this paper, we illustrate how state-of-the-art open source computational modelling and simulation tools can be used to simulate multi-scale effects of drug-induced ion channel block in ventricular electrophysiology at the cellular, tissue and whole ventricular levels for different animal species. We believe that the use of computational modelling and simulation in combination with experimental techniques could be a powerful tool for the assessment of drug safety pharmacology
Electrophysiology Model for a Human Heart with Ischemic Scar and Realistic Purkinje Network
The role of Purkinje fibres in the onset of arrhythmias is controversial and computer simulations may shed light on possible arrhythmic mechanisms involving the Purkinje fibres. However, few computational modelling studies currently include a detailed Purkinje network as part of the model. We present a coupled Purkinje-myocardium electrophysiology model that includes an explicit model for the ischemic scar plus a detailed Purkinje network, and compare simulated activation times to those obtained by electro-anatomical mapping in vivo during sinus rhythm pacing. The results illustrate the importance of using sufficiently dense Purkinje networks in patient-specific studies to capture correctly the myocardial early activation that may be influenced by surviving Purkinje fibres in the infarct region
Thyroid hormone metabolism and environmental chemical exposure
<p>Abstract</p> <p>Background</p> <p>Polychlorinated dioxins and –furans (PCDD/Fs) and polychlorinated-biphenyls (PCBs) are environmental toxicants that have been proven to influence thyroid metabolism both in animal studies and in human beings. In recent years polybrominated diphenyl ethers (PBDEs) also have been found to have a negative influence on thyroid hormone metabolism. The lower brominated flame retardants are now banned in the EU, however higher brominated decabromo-diphenyl ether (DBDE) and the brominated flame retardant hexabromocyclododecane (HBCD) are not yet banned. They too can negatively influence thyroid hormone metabolism. An additional brominated flame retardant that is still in use is tetrabromobisphenol-A (TBBPA), which has also been shown to influence thyroid hormone metabolism.</p> <p>Influences of brominated flame retardants, PCDD/F’s and dioxin like-PCBs (dl-PCB’s) on thyroid hormone metabolism in adolescence in the Netherlands will be presented in this study and determined if there are reasons for concern to human health for these toxins. In the period 1987-1991, a cohort of mother-baby pairs was formed in order to detect abnormalities in relation to dioxin levels in the perinatal period. The study demonstrated that PCDD/Fs were found around the time of birth, suggesting a modulation of the setpoint of thyroid hormone metabolism with a higher 3,3’, 5,5’tetrathyroxine (T4) levels and an increased thyroid stimulating hormone (TSH). While the same serum thyroid hormone tests (- TSH and T4) were again normal by 2 years of age and were still normal at 8-12 years, adolescence is a period with extra stress on thyroid hormone metabolism. Therefore we measured serum levels of TSH, T4, 3,3’,5- triiodothyronine (T3), free T4 (FT4), antibodies and thyroxine-binding globulin (TBG) in our adolescent cohort.</p> <p>Methods</p> <p>Vena puncture was performed to obtain samples for the measurement of thyroid hormone metabolism related parameters and the current serum dioxin (PCDD/Fs), PCB and PBDE levels.</p> <p>Results</p> <p>The current levels of T3 were positively correlated to BDE-99. A positive trend with FT4 and BDE-99 was also seen, while a positive correlation with T3 and dl-PCB was also seen. No correlation with TBG was seen for any of the contaminants. Neither the prenatal nor the current PCDD/F levels showed a relationship with the thyroid parameters in this relatively small group.</p> <p>Conclusion</p> <p>Once again the thyroid hormone metabolism (an increase in T3) seems to have been influenced by current background levels of common environmental contaminants: dl-PCBs and BDE-99. T3 is a product of target organs and abnormalities might indicate effects on hormone transporters and could cause pathology. While the influence on T3 levels may have been compensated, because the adolescents functioned normal at the time of the study period, it is questionable if this compensation is enough for all organs depending on thyroid hormones.</p
Fully-Coupled Electromechanical Simulations of the LV Dog Anatomy Using HPC: Model Testing and Verification
Verification of electro-mechanic models of the heart require a good amount of reliable, high resolution, thorough in-vivo measurements. The detail of the mathematical models used to create simulations of the heart beat vary greatly. Generally, the objective of the simulation determines the modeling approach. However, it is important to exactly quantify the amount of error between the various approaches that can be used to simulate a heart beat by comparing them to ground truth data. The more detailed the model is, the more computing power it requires, we therefore employ a high-performance computing solver throughout this study. We aim to compare models to data measured experimentally to identify the effect of using a mathematical model of fibre orientation versus the measured fibre orientations using DT-MRI. We also use simultaneous endocardial stimuli vs an instantaneous myocardial stimulation to trigger the mechanic contraction. Our results show that synchronisation of the electrical and mechanical events in the heart beat are necessary to create a physiological timing of hemodynamic events. Synchronous activation of all of the myocardium provides an unrealistic timing of hemodynamic events in the cardiac cycle. Results also show the need of establishing a protocol to quantify the zero-pressure configuration of the left ventricular geometry to initiate the simulation protocol; however, the predicted zero-pressure configuration of the same geometry was different, depending on the origin of the fibre field employed.This work has been done with the support of the grant SEV-2011-00067 of Severo Ochoa Program, awarded by the Spanish Government to the Barcelona Supercomputing Center. Part of the research leading to these results has received funding from the Seventh Framework Programme (FP7/2007-2013) under grant agreement n 611823. It has also been partially funded from the by the Spanish
Ministry of Economy and Competitiveness (TIN2011-28067).Peer ReviewedPostprint (author's final draft
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
Evolution of spiral and scroll waves of excitation in a mathematical model of ischaemic border zone
Abnormal electrical activity from the boundaries of ischemic cardiac tissue
is recognized as one of the major causes in generation of ischemia-reperfusion
arrhythmias. Here we present theoretical analysis of the waves of electrical
activity that can rise on the boundary of cardiac cell network upon its
recovery from ischaemia-like conditions. The main factors included in our
analysis are macroscopic gradients of the cell-to-cell coupling and cell
excitability and microscopic heterogeneity of individual cells. The interplay
between these factors allows one to explain how spirals form, drift together
with the moving boundary, get transiently pinned to local inhomogeneities, and
finally penetrate into the bulk of the well-coupled tissue where they reach
macroscopic scale. The asymptotic theory of the drift of spiral and scroll
waves based on response functions provides explanation of the drifts involved
in this mechanism, with the exception of effects due to the discreteness of
cardiac tissue. In particular, this asymptotic theory allows an extrapolation
of 2D events into 3D, which has shown that cells within the border zone can
give rise to 3D analogues of spirals, the scroll waves. When and if such scroll
waves escape into a better coupled tissue, they are likely to collapse due to
the positive filament tension. However, our simulations have shown that such
collapse of newly generated scrolls is not inevitable and that under certain
conditions filament tension becomes negative, leading to scroll filaments to
expand and multiply leading to a fibrillation-like state within small areas of
cardiac tissue.Comment: 26 pages, 13 figures, appendix and 2 movies, as accepted to PLoS ONE
2011/08/0
- …