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

Anti-phase synchronization of phase-reduced oscillators using open-loop control

In this letter, we present an elegant method to build and maintain an anti-phase configuration of two nonlinear oscillators with different natural frequencies and dynamics described by the sinusoidal phase-reduced model. The anti-phase synchronization is achieved using a common input that couples the oscillators and consists of a sequence of square pulses of appropriate amplitude and duration. This example provides a proof of principle that open-loop control can be used to create desired synchronization patterns for nonlinear oscillators, when feedback is expensive or impossible to obtain

Noise Effects on the Complex Patterns of Abnormal Heartbeats

Patients at high risk for sudden death often exhibit complex heart rhythms in which abnormal heartbeats are interspersed with normal heartbeats. We analyze such a complex rhythm in a single patient over a 12-hour period and show that the rhythm can be described by a theoretical model consisting of two interacting oscillators with stochastic elements. By varying the magnitude of the noise, we show that for an intermediate level of noise, the model gives best agreement with key statistical features of the dynamics.Comment: 4 pages, 4 figures, RevTe

A null mutation of the neuronal sodium channel NaV1.6 disrupts action potential propagation and excitation‐contraction coupling in the mouse heart

Evidence supports the expression of brain‐type sodium channels in the heart. Their functional role, however, remains controversial. We used global NaV1.6‐null mice to test the hypothesis that NaV1.6 contributes to the maintenance of propagation in the myocardium and to excitation‐contraction (EC) coupling. We demonstrated expression of transcripts encoding full‐length NaV1.6 in isolated ventricular myocytes and confirmed the striated pattern of NaV1.6 fluorescence in myocytes. On the ECG, the PR and QRS intervals were prolonged in the null mice, and the Ca2+ transients were longer in the null cells. Under patch clamping, at holding potential (HP) = –120 mV, the peak INa was similar in both phenotypes. However, at HP = –70 mV, the peak INa was smaller in the nulls. In optical mapping, at 4 mM [K+]o, 17 null hearts showed slight (7%) reduction of ventricular conduction velocity (CV) compared to 16 wild‐type hearts. At 12 mM [K+]o, CV was 25% slower in a subset of 9 null vs. 9 wild‐type hearts. These results highlight the importance of neuronal sodium channels in the heart, whereby NaV1.6 participates in EC coupling, and represents an intrinsic depolarizing reserve that contributes to excitation.—Noujaim, S. F., Kaur, K., Milstein, M., Jones, J. M., Furspan, P., Jiang, D., Auerbach, D. S., Herron, T., Meisler, M. H., Jalife, J. A null mutation of the neuronal sodium channel NaV1.6 disrupts action potential propagation and excitation‐contraction coupling in the mouse heart. FASEB J. 26, 63–72 (2012). www.fasebj.orgPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154524/1/fsb2fj10179770.pd

Electrophysiological characteristics of permanent atrial fibrillation: insights from research models of cardiac remodeling

[EN] Atrial fibrillation (AF) results in a remodeling of the electrical and structural characteristics of the cardiac tissue which dramatically reduces the efficacy of pharmacological and catheter-based ablation therapies. Recent experimental and clinical results have demonstrated that the complexity of the fibrillatory process significantly differs in paroxysmal versus persistent AF; however, the lack of appropriate research models of remodeled atrial tissue precludes the elucidation of the underlying AF mechanisms and the identification of appropriated therapeutic targets. Here, we summarize the different research models used to date, highlighting the lessons learned from them and pointing to the new doors that should be open for the development of innovative treatments for AF.The authors were supported by grants from the Spanish Ministry of Science and Innovation (PLE2009-0152), the Instituto de Salud Carlos III (Ministry of Economy and Competitiveness, Spain: PI13-01882 and PI13-00903) the Red de Investigacion Cardiovacular (RIC) from Instituto de Salud Carlos III (Ministry of Economy and Competitiveness, Spain). F Atienza served on the advisory board of Medtronic and has received research funding from St. Jude Medical Spain. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Climent, A.; Guillem Sánchez, MS.; Atienza Fernández, F.; Fernandez-Aviles, F. (2014). Electrophysiological characteristics of permanent atrial fibrillation: insights from research models of cardiac remodeling. Expert Review of Cardiovascular Therapy. 13(1):1-3. https://doi.org/10.1586/14779072.2015.986465S1313

Body surface localization of left and right atrial high-frequency rotors in atrial fibrillation patients: A clinical-computational study

Background: Ablation is an effective therapy in atrial fibrillation (AF) patients in which an electrical driver can be identified. Objective: The aim of this study is to present and discuss a novel and strictly non-invasive approach to map and identify atrial regions responsible for AF perpetuation. Methods: Surface potential recordings of 14 patients with AF were recorded using a 67-lead recording system. Singularity points (SPs) were identified in surface phase maps after band-pass filtering at the highest dominant frequency (HDF). Mathematical models of combined atria and torso were constructed and used to investigate the ability of surface phase maps to estimate rotor activity in the atrial wall. Results: The simulations show that surface SPs originate at atrial SPs, but not all atrial SPs are reflected at the surface. Stable SPs were found in AF signals during 8.3±5.7% vs. 73.1±16.8% of the time in unfiltered vs. HDF-filtered patient data respectively (p<0.01). The average duration of each rotational pattern was also lower in unfiltered than in HDF-filtered AF signals (160±43 vs. 342±138 ms, p<0.01) resulting in 2.8±0.7 rotations per rotor. Band-pass filtering reduced the apparent meandering of surface HDF rotors by reducing the effect of the atrial electrical activity taking place at different frequencies. Torso surface SPs representing HDF rotors during AF were reflected at specific areas corresponding to the fastest atrial location. Conclusion: Phase analysis of surface potential signals after HDF-filtering during AF shows reentrant drivers localized to either the LA or RA, helping in localizing ablation targetsThis work was supported in part by the Spanish Society of Cardiology (Becas Investigacion Clinica 2009); the Universitat Politecnica de Valencia through its research initiative program; the Generalitat Valenciana grant (ACIF/2013/021); the Ministerio de Economia y Competitividad, Rod RIC; the Centro Nacional de Investigaciones Cardiovasculares (proyecto CNIC-13); the Coulter Foundation from the Biomedical Engineering Department, University of Michigan; the Gelman Award from the Cardiovascular Division, University of Michigan; the National Heart, Lung, and Blood Institute grants (P01411.039707, P01-1111187226, and R01-11L118304); and the Leducq Foundation. Dr Femandez-Aviles served on the advisory board of Medtronic and has received research funding from St Jude Medical Spain. Dr Berenfeld has received research support from Medtronic and St Jude Medical; he is a colbunder and scientific officer of Rhythm Solutions. None of the companies disclosed financed the research described in this article.Rodrigo Bort, M.; Guillem Sánchez, MS.; Climent, AM.; Pedrón Torrecilla, J.; Liberos Mascarell, A.; Millet Roig, J.; Fernandez-Aviles, F.... (2014). Body surface localization of left and right atrial high-frequency rotors in atrial fibrillation patients: A clinical-computational study. Heart Rhythm. 11(9):1584-1591. https://doi.org/10.1016/j.hrthm.2014.05.013S1584159111

Role of extracellular histones in the cardiomyopathy of sepsis

The purpose of this study was to define the relationship in polymicrobial sepsis (in adult male C57BL/6 mice) between heart dysfunction and the appearance in plasma of extracellular histones. Procedures included induction of sepsis by cecal ligation and puncture and measurement of heart function using echocardiogram/Doppler parameters. We assessed the ability of histones to cause disequilibrium in the redox status and intracellular [Ca2+]i levels in cardiomyocytes (CMs) (from mice and rats). We also studied the ability of histones to disturb both functional and electrical responses of hearts perfused with histones. Main findings revealed that extracellular histones appearing in septic plasma required C5a receptors, polymorphonuclear leukocytes (PMNs), and the Nachtâ , LRRâ , and PYDâ domainsâ containing protein 3 (NLRP3) inflammasome. In vitro exposure of CMs to histones caused loss of homeostasis of the redox system and in [Ca2+]i, as wellas defects in mitochondrial function. Perfusion of hearts with histones caused electrical and functional dysfunction. Finally, in vivo neutralization of histones in septic mice markedly reduced the parameters of heart dysfunction. Histones caused dysfunction in hearts during polymicrobial sepsis. These events could be attenuated by histone neutralization, suggesting that histones may be targets in the setting of sepsis to reduce cardiac dysfunction.â Kalbitz, M., Grailer, J. J., Fattahi, F., Jajou, L., Herron, T. J., Campbell, K. F., Zetoune, F. S., Bosmann, M., Sarma, J. V., Huberâ Lang, M., Gebhard, F., Loaiza, R., Valdivia, H. H., Jalife, J., Russell, M. W., Ward, P. A. Role of extracellular histones in the cardiomyopathy of sepsis. FASEB J. 29, 2185â 2193 (2015). www.fasebj.orgPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154273/1/fsb2fj14268730.pd

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

Spiral anchoring in anisotropic media with multiple inhomogeneities: a dynamical system approach

Various PDE models have been suggested in order to explain and predict the dynamics of spiral waves in excitable media. In two landmark papers, Barkley noticed that some of the behaviour could be explained by the inherent Euclidean symmetry of these models. LeBlanc and Wulff then introduced forced Euclidean symmetry-breaking (FESB) to the analysis, in the form of individual translational symmetry-breaking (TSB) perturbations and rotational symmetry-breaking (RSB) perturbations; in either case, it is shown that spiral anchoring is a direct consequence of the FESB. In this article, we provide a characterization of spiral anchoring when two perturbations, a TSB term and a RSB term, are combined, where the TSB term is centered at the origin and the RSB term preserves rotations by multiples of $\frac{2\pi}{\jmath^*}$, where $\jmath^*\geq 1$ is an integer. When $\jmath^*>1$ (such as in a modified bidomain model), it is shown that spirals anchor at the origin, but when $\jmath^* =1$ (such as in a planar reaction-diffusion-advection system), spirals generically anchor away from the origin.Comment: Revised versio