Response to sub-threshold stimulus is enhanced by spatially heterogeneous activity

Sub-threshold stimuli cannot initiate excitations in active media, but surprisingly as we show in this paper, they can alter the time-evolution of spatially heterogeneous activity by modifying the recovery dynamics. This results in significant reduction of waveback velocity which may lead to spatial coherence, terminating all activity in the medium including spatiotemporal chaos. We analytically derive model-independent conditions for which such behavior can be observed.Comment: 5 pages, 5 figure

Predicting outcome of rethoracotomy for suspected pericardial tamponade following cardio-thoracic surgery in the intensive care unit

<p>Abstract</p> <p>Objectives</p> <p>Pericardial tamponade after cardiac surgery is difficult to diagnose, thereby rendering timing of rethoracotomy hard. We aimed at identifying factors predicting the outcome of surgery for suspected tamponade after cardio-thoracic surgery, in the intensive care unit (ICU).</p> <p>Methods</p> <p>Twenty-one consecutive patients undergoing rethoracotomy for suspected pericardial tamponade in the ICU, admitted after primary cardio-thoracic surgery, were identified for this retrospective study. We compared patients with or without a decrease in severe haemodynamic compromise after rethoracotomy, according to the cardiovascular component of the sequential organ failure assessment (SOFA) score.</p> <p>Results</p> <p>A favourable haemodynamic response to rethoracotomy was observed in 11 (52%) of patients and characterized by an increase in cardiac output, and less fluid and norepinephrine requirements. Prior to surgery, the absence of treatment by heparin, a minimum cardiac index < 1.0 L/min/m²and a positive fluid balance (> 4,683 mL) were predictive of a beneficial haemodynamic response. During surgery, the evacuation of clots and > 500 mL of pericardial fluid was associated with a beneficial haemodynamic response. Echocardiographic parameters were of limited help in predicting the postoperative course, even though 9 of 13 pericardial clots found at surgery were detected preoperatively.</p> <p>Conclusion</p> <p>Clots and fluids in the pericardial space causing regional tamponade and responding to surgical evacuation after primary cardio-thoracic surgery, are difficult to diagnose preoperatively, by clinical, haemodynamic and even echocardiographic evaluation in the ICU. Only absence of heparin treatment, a large positive fluid balance and low cardiac index predicted a favourable haemodynamic response to rethoracotomy. These data might help in deciding and timing of reinterventions after primary cardio-thoracic surgery.</p

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

Persistent hematologic and immunologic disturbances in 8-year-old Dutch children associated with perinatal dioxin exposure.

Perinatal exposure to Dutch "background" dioxin levels in 1990 was high, but comparable with that of other industrialized Western European countries. Exposure during the sensitive perinatal period may cause permanent disturbances. Therefore, we assessed the health status and various hematologic and immunologic parameters among our longitudinal cohort. A medical history was taken and venipuncture performed in a longitudinal cohort of 27 healthy 8-year-old children who had documented perinatal dioxin exposure. Linear regression revealed a decrease in allergy in relation to prenatal (p = 0.02) and postnatal (p = 0.03) dioxin exposure. Increases in CD4+ T-helper cells (p = 0.006) and in CD45RA+ cells (p = 0.02) were seen in relation to postnatal exposure. A persistently decreased platelet count (p = 0.04) and increased thrombopoietin concentration (p = 0.03) were seen in relation to postnatal exposure. This follow-up has shown a decrease in allergy, persistently decreased thrombocytes, increased thrombopoietin, and increased CD4+ T-helper and increased CD45RA+ cell counts. This study provides indications of effects at the stem cell level of perinatal dioxin exposure, persisting until minimally 8 years after birth

In silico investigation of a KCNQ1 mutation associated with short QT syndrome

Short QT syndrome (SQTS) is a rare condition characterized by abnormally ‘short’ QT intervals on the ECG and increased susceptibility to cardiac arrhythmias and sudden death. This simulation study investigated arrhythmia dynamics in multi-scale human ventricle models associated with the SQT2-related V307L KCNQ1 ‘gain-of-function’ mutation, which increases slow-delayed rectifier potassium current (IKs). A Markov chain (MC) model recapitulating wild type (WT) and V307L mutant IKs kinetics was incorporated into a model of the human ventricular action potential (AP) for investigation of QT interval changes and arrhythmia substrates. In addition, the degree of simulated IKs inhibition necessary to normalize the QT interval and terminate re-entry in SQT2 conditions was quantified. The developed MC model accurately reproduced AP shortening and reduced effective refractory period associated with altered IKs kinetics in homozygous (V307L) and heterozygous (WT-V307L) mutation conditions, which increased the lifespan and dominant frequency of re-entry in 3D human ventricle models. IKs reductions of 58% and 65% were sufficient to terminate re-entry in WT-V307L and V307L conditions, respectively. This study further substantiates a causal link between the V307L KCNQ1 mutation and pro-arrhythmia in human ventricles, and establishes partial inhibition of IKs as a potential anti-arrhythmic strategy in SQT2

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

Spiral-Wave Turbulence and Its Control in the Presence of Inhomogeneities in Four Mathematical Models of Cardiac Tissue

Regular electrical activation waves in cardiac tissue lead to the rhythmic contraction and expansion of the heart that ensures blood supply to the whole body. Irregularities in the propagation of these activation waves can result in cardiac arrhythmias, like ventricular tachycardia (VT) and ventricular fibrillation (VF), which are major causes of death in the industrialised world. Indeed there is growing consensus that spiral or scroll waves of electrical activation in cardiac tissue are associated with VT, whereas, when these waves break to yield spiral- or scroll-wave turbulence, VT develops into life-threatening VF: in the absence of medical intervention, this makes the heart incapable of pumping blood and a patient dies in roughly two-and-a-half minutes after the initiation of VF. Thus studies of spiral- and scroll-wave dynamics in cardiac tissue pose important challenges for in vivo and in vitro experimental studies and for in silico numerical studies of mathematical models for cardiac tissue. A major goal here is to develop low-amplitude defibrillation schemes for the elimination of VT and VF, especially in the presence of inhomogeneities that occur commonly in cardiac tissue. We present a detailed and systematic study of spiral- and scroll-wave turbulence and spatiotemporal chaos in four mathematical models for cardiac tissue, namely, the Panfilov, Luo-Rudy phase 1 (LRI), reduced Priebe-Beuckelmann (RPB) models, and the model of ten Tusscher, Noble, Noble, and Panfilov (TNNP). In particular, we use extensive numerical simulations to elucidate the interaction of spiral and scroll waves in these models with conduction and ionic inhomogeneities; we also examine the suppression of spiral- and scroll-wave turbulence by low-amplitude control pulses. Our central qualitative result is that, in all these models, the dynamics of such spiral waves depends very sensitively on such inhomogeneities. We also study two types of control schemes that have been suggested for the control of spiral turbulence, via low amplitude current pulses, in such mathematical models for cardiac tissue; our investigations here are designed to examine the efficacy of such control schemes in the presence of inhomogeneities. We find that a local pulsing scheme does not suppress spiral turbulence in the presence of inhomogeneities; but a scheme that uses control pulses on a spatially extended mesh is more successful in the elimination of spiral turbulence. We discuss the theoretical and experimental implications of our study that have a direct bearing on defibrillation, the control of life-threatening cardiac arrhythmias such as ventricular fibrillation