Global alternans instability and its effect on non-linear wave propagation : dynamical Wenckebach block and self terminating spiral waves

The main mechanism of formation of reentrant cardiac arrhythmias is via formation of waveblocks at heterogeneities of cardiac tissue. We report that heterogeneity and the area of waveblock can extend itself in space and can result formation of new additional sources, or termination of existing sources of arrhythmias. This effect is based on a new form of instability, which we coin as global alternans instability (GAI). GAI is closely related to the so-called (discordant) alternans instability, however its onset is determined by the global properties of the APD-restitution curve and not by its slope. The APD-restitution curve relates the duration of the cardiac pulse (APD) to the time interval between the pulses, and can easily be measured in an experimental or even clinical setting. We formulate the conditions for the onset of GAI, study its manifestation in various 1D and 2D situations and discuss its importance for the onset of cardiac arrhythmias

The Calcineurin-FoxO-MuRF1 signaling pathway regulates myofibril integrity in cardiomyocytes.

Altered Ca2+ handling is often present in diseased hearts undergoing structural remodeling and functional deterioration. However, whether Ca2+ directly regulates sarcomere structure has remained elusive. Using a zebrafish ncx1 mutant, we explored the impacts of impaired Ca2+ homeostasis on myofibril integrity. We found that the E3 ubiquitin ligase murf1 is upregulated in ncx1-deficient hearts. Intriguingly, knocking down murf1 activity or inhibiting proteasome activity preserved myofibril integrity, revealing a MuRF1-mediated proteasome degradation mechanism that is activated in response to abnormal Ca2+ homeostasis. Furthermore, we detected an accumulation of the murf1 regulator FoxO in the nuclei of ncx1-deficient cardiomyocytes. Overexpression of FoxO in wild type cardiomyocytes induced murf1 expression and caused myofibril disarray, whereas inhibiting Calcineurin activity attenuated FoxO-mediated murf1 expression and protected sarcomeres from degradation in ncx1-deficient hearts. Together, our findings reveal a novel mechanism by which Ca2+ overload disrupts myofibril integrity by activating a Calcineurin-FoxO-MuRF1-proteosome signaling pathway

Update on antiarrhythmic drug pharmacology.

Cardiac arrhythmias constitute a major public health problem. Pharmacological intervention remains mainstay to their clinical management. This, in turn, depends upon systematic drug classification schemes relating their molecular, cellular, and systems effects to clinical indications and therapeutic actions. This approach was first pioneered in the 1960s Vaughan-Williams classification. Subsequent progress in cardiac electrophysiological understanding led to a lag between the fundamental science and its clinical translation, partly addressed by The working group of the European Society of Cardiology (1991), which, however, did not emerge with formal classifications. We here utilize the recent Revised Oxford Classification Scheme to review antiarrhythmic drug pharmacology. We survey drugs and therapeutic targets offered by the more recently characterized ion channels, transporters, receptors, intracellular Ca2+ handling, and cell signaling molecules. These are organized into their strategic roles in cardiac electrophysiological function. Following analysis of the arrhythmic process itself, we consider (a) pharmacological agents directly targeting membrane function, particularly the Na+ and K+ ion channels underlying depolarizing and repolarizing events in the cardiac action potential. (b) We also consider agents that modify autonomic activity that, in turn, affects both the membrane and (c) the Ca2+ homeostatic and excitation-contraction coupling processes linking membrane excitation to contractile activation. Finally, we consider (d) drugs acting on more upstream energetic and structural remodeling processes currently the subject of clinical trials. Such systematic correlations of drug actions and arrhythmic mechanisms at different molecular to systems levels of cardiac function will facilitate current and future antiarrhythmic therapy

Computer simulation of syringomyelia in dogs

Syringomyelia is a pathological condition in which fluid-filled cavities (syringes) form and expand in the spinal cord. Syringomyelia is often linked with obstruction of the craniocervical junction and a Chiari malformation, which is similar in both humans and animals. Some brachycephalic toy breed dogs such as Cavalier King Charles Spaniels (CKCS) are particularly predisposed. The exact mechanism of the formation of syringomyelia is undetermined and consequently with the lack of clinical explanation, engineers and mathematicians have resorted to computer models to identify possible physical mechanisms that can lead to syringes. We developed a computer model of the spinal cavity of a CKCS suffering from a large syrinx. The model was excited at the cranial end to simulate the movement of the cerebrospinal fluid (CSF) and the spinal cord due to the shift of blood volume in the cranium related to the cardiac cycle. To simulate the normal condition, the movement was prescribed to the CSF. To simulate the pathological condition, the movement of CSF was blocked

Modelling the effect of gap junctions on tissue-level cardiac electrophysiology

When modelling tissue-level cardiac electrophysiology, continuum approximations to the discrete cell-level equations are used to maintain computational tractability. One of the most commonly used models is represented by the bidomain equations, the derivation of which relies on a homogenisation technique to construct a suitable approximation to the discrete model. This derivation does not explicitly account for the presence of gap junctions connecting one cell to another. It has been seen experimentally [Rohr, Cardiovasc. Res. 2004] that these gap junctions have a marked effect on the propagation of the action potential, specifically as the upstroke of the wave passes through the gap junction. In this paper we explicitly include gap junctions in a both a 2D discrete model of cardiac electrophysiology, and the corresponding continuum model, on a simplified cell geometry. Using these models we compare the results of simulations using both continuum and discrete systems. We see that the form of the action potential as it passes through gap junctions cannot be replicated using a continuum model, and that the underlying propagation speed of the action potential ceases to match up between models when gap junctions are introduced. In addition, the results of the discrete simulations match the characteristics of those shown in Rohr 2004. From this, we suggest that a hybrid model -- a discrete system following the upstroke of the action potential, and a continuum system elsewhere -- may give a more accurate description of cardiac electrophysiology.Comment: In Proceedings HSB 2012, arXiv:1208.315

A modeling framework for contact, adhesion and mechano-transduction between excitable deformable cells

Cardiac myocytes are the fundamental cells composing the heart muscle. The propagation of electric signals and chemical quantities through them is responsible for their nonlinear contraction and dilatation. In this study, a theoretical model and a finite element formulation are proposed for the simulation of adhesive contact interactions between myocytes across the so-called gap junctions. A multi-field interface constitutive law is proposed for their description, integrating the adhesive and contact mechanical response with their electrophysiological behavior. From the computational point of view, the initial and boundary value problem is formulated as a structure-structure interaction problem, which leads to a straightforward implementation amenable for parallel computations. Numerical tests are conducted on different couples of myocytes, characterized by different shapes related to their stages of growth, capturing the experimental response. The proposed framework is expected to have impact on the understanding how imperfect mechano-transduction could lead to emergent pathological responses.Comment: 31 pages, 17 figure

International criteria for electrocardiographic interpretation in athletes: Consensus statement.

Sudden cardiac death (SCD) is the leading cause of mortality in athletes during sport. A variety of mostly hereditary, structural or electrical cardiac disorders are associated with SCD in young athletes, the majority of which can be identified or suggested by abnormalities on a resting 12-lead electrocardiogram (ECG). Whether used for diagnostic or screening purposes, physicians responsible for the cardiovascular care of athletes should be knowledgeable and competent in ECG interpretation in athletes. However, in most countries a shortage of physician expertise limits wider application of the ECG in the care of the athlete. A critical need exists for physician education in modern ECG interpretation that distinguishes normal physiological adaptations in athletes from distinctly abnormal findings suggestive of underlying pathology. Since the original 2010 European Society of Cardiology recommendations for ECG interpretation in athletes, ECG standards have evolved quickly, advanced by a growing body of scientific data and investigations that both examine proposed criteria sets and establish new evidence to guide refinements. On 26-27 February 2015, an international group of experts in sports cardiology, inherited cardiac disease, and sports medicine convened in Seattle, Washington (USA), to update contemporary standards for ECG interpretation in athletes. The objective of the meeting was to define and revise ECG interpretation standards based on new and emerging research and to develop a clear guide to the proper evaluation of ECG abnormalities in athletes. This statement represents an international consensus for ECG interpretation in athletes and provides expert opinion-based recommendations linking specific ECG abnormalities and the secondary evaluation for conditions associated with SCD

Analytically Solvable Asymptotic Model of Atrial Excitability

We report a three-variable simplified model of excitation fronts in human atrial tissue. The model is derived by novel asymptotic techniques \new{from the biophysically realistic model of Courtemanche et al (1998) in extension of our previous similar models. An iterative analytical solution of the model is presented which is in excellent quantitative agreement with the realistic model. It opens new possibilities for analytical studies as well as for efficient numerical simulation of this and other cardiac models of similar structure

Asymptotics of conduction velocity restitution in models of electrical excitation in the heart

We extend a non-Tikhonov asymptotic embedding, proposed earlier, for calculation of conduction velocity restitution curves in ionic models of cardiac excitability. Conduction velocity restitution is the simplest non-trivial spatially extended problem in excitable media, and in the case of cardiac tissue it is an important tool for prediction of cardiac arrhythmias and fibrillation. An idealized conduction velocity restitution curve requires solving a non-linear eigenvalue problem with periodic boundary conditions, which in the cardiac case is very stiff and calls for the use of asymptotic methods. We compare asymptotics of restitution curves in four examples, two generic excitable media models, and two ionic cardiac models. The generic models include the classical FitzHugh–Nagumo model and its variation by Barkley. They are treated with standard singular perturbation techniques. The ionic models include a simplified “caricature” of Noble (J. Physiol. Lond. 160:317–352, 1962) model and Beeler and Reuter (J. Physiol. Lond. 268:177–210, 1977) model, which lead to non-Tikhonov problems where known asymptotic results do not apply. The Caricature Noble model is considered with particular care to demonstrate the well-posedness of the corresponding boundary-value problem. The developed method for calculation of conduction velocity restitution is then applied to the Beeler–Reuter model. We discuss new mathematical features appearing in cardiac ionic models and possible applications of the developed method