HD Physiology Project-Japanese efforts to promote multilevel integrative systems biology and physiome research.

The HD Physiology Project is a Japanese research consortium that aimed to develop methods and a computational platform in which physiological and pathological information can be described in high-level definitions across multiple scales of time and size. During the 5 years of this project, an appropriate software platform for multilevel functional simulation was developed and a whole-heart model including pharmacokinetics for the assessment of the proarrhythmic risk of drugs was developed. In this article, we outline the description and scientific strategy of this project and present the achievements and influence on multilevel integrative systems biology and physiome research

Facilitation of I Kr current by some hERG channel blockers suppresses early afterdepolarizations.

Drug-induced block of the cardiac rapid delayed rectifying potassium current (I Kr), carried by the human ether-a-go-go-related gene (hERG) channel, is the most common cause of acquired long QT syndrome. Indeed, some, but not all, drugs that block hERG channels cause fatal cardiac arrhythmias. However, there is no clear method to distinguish between drugs that cause deadly arrhythmias and those that are clinically safe. Here we propose a mechanism that could explain why certain clinically used hERG blockers are less proarrhythmic than others. We demonstrate that several drugs that block hERG channels, but have favorable cardiac safety profiles, also evoke another effect; they facilitate the hERG current amplitude in response to low-voltage depolarization. To investigate how hERG facilitation impacts cardiac safety, we develop computational models of I Kr block with and without this facilitation. We constrain the models using data from voltage clamp recordings of hERG block and facilitation by nifekalant, a safe class III antiarrhythmic agent. Human ventricular action potential simulations demonstrate the ability of nifekalant to suppress ectopic excitations, with or without facilitation. Without facilitation, excessive I Kr block evokes early afterdepolarizations, which cause lethal arrhythmias. When facilitation is introduced, early afterdepolarizations are prevented at the same degree of block. Facilitation appears to prevent early afterdepolarizations by increasing I Kr during the repolarization phase of action potentials. We empirically test this prediction in isolated rabbit ventricular myocytes and find that action potential prolongation with nifekalant is less likely to induce early afterdepolarization than action potential prolongation with dofetilide, a hERG channel blocker that does not induce facilitation. Our data suggest that hERG channel blockers that induce facilitation increase the repolarization reserve of cardiac myocytes, rendering them less likely to trigger lethal ventricular arrhythmias

Modeling Light Adaptation in Circadian Clock: Prediction of the Response That Stabilizes Entrainment

Periods of biological clocks are close to but often different from the rotation period of the earth. Thus, the clocks of organisms must be adjusted to synchronize with day-night cycles. The primary signal that adjusts the clocks is light. In Neurospora, light transiently up-regulates the expression of specific clock genes. This molecular response to light is called light adaptation. Does light adaptation occur in other organisms? Using published experimental data, we first estimated the time course of the up-regulation rate of gene expression by light. Intriguingly, the estimated up-regulation rate was transient during light period in mice as well as Neurospora. Next, we constructed a computational model to consider how light adaptation had an effect on the entrainment of circadian oscillation to 24-h light-dark cycles. We found that cellular oscillations are more likely to be destabilized without light adaption especially when light intensity is very high. From the present results, we predict that the instability of circadian oscillations under 24-h light-dark cycles can be experimentally observed if light adaptation is altered. We conclude that the functional consequence of light adaptation is to increase the adjustability to 24-h light-dark cycles and then adapt to fluctuating environments in nature

Bifurcations and Proarrhythmic Behaviors in Cardiac Electrical Excitations

The heart is a hierarchical dynamic system consisting of molecules, cells, and tissues, and acts as a pump for blood circulation. The pumping function depends critically on the preceding electrical activity, and disturbances in the pattern of excitation propagation lead to cardiac arrhythmia and pump failure. Excitation phenomena in cardiomyocytes have been modeled as a nonlinear dynamical system. Because of the nonlinearity of excitation phenomena, the system dynamics could be complex, and various analyses have been performed to understand the complex dynamics. Understanding the mechanisms underlying proarrhythmic responses in the heart is crucial for developing new ways to prevent and control cardiac arrhythmias and resulting contractile dysfunction. When the heart changes to a pathological state over time, the action potential (AP) in cardiomyocytes may also change to a different state in shape and duration, often undergoing a qualitative change in behavior. Such a dynamic change is called bifurcation. In this review, we first summarize the contribution of ion channels and transporters to AP formation and our knowledge of ion-transport molecules, then briefly describe bifurcation theory for nonlinear dynamical systems, and finally detail its recent progress, focusing on the research that attempts to understand the developing mechanisms of abnormal excitations in cardiomyocytes from the perspective of bifurcation phenomena

Bifurcation analyses of nonlinear dynamical systems : From theory to numerical computations

In this paper, we explain how to compute bifurcation parameter values of periodic solutions for non-autonomous nonlinear differential equations. Although various approaches and tools are available for solving this problem nowadays, we have devised a very simple method composed only of basic computational algorithms appearing in textbooks for beginner's, i.e., Newton's method and the Runge-Kutta method. We formulate the bifurcation problem as a boundary value problem and use Newton's method as a solver consistently. All derivatives required in each iteration are obtained by solving variational equations about the state and the parameter. Thanks to the quadratic convergence ability of Newton's method, accurate results can be quickly and effectively obtained without using any sophisticated mathematical library or software. If a discontinuous periodic force is applied to the system, we can use the same strategy to solve the bifurcation problem. The key point of this method is deriving a differentiable composite map from the various information about the problem such as the location of sections, the periodicity, the Poincaré mapping, etc

Hysteretic Dynamics of Multi-Stable Early Afterdepolarisations with Repolarisation Reserve Attenuation: A Potential Dynamical Mechanism for Cardiac Arrhythmias

Abstract Some cardiovascular and non-cardiovascular drugs frequently cause excessive prolongation of the cardiac action potential (AP) and lead to the development of early afterdepolarisations (EADs), which trigger lethal ventricular arrhythmias. Combining computer simulations in APs with numerical calculations based on dynamical system theory, we investigated stability changes of APs observed in a paced human ventricular myocyte model by decreasing and/or increasing the rapid (I Kr) and slow (I Ks) components of delayed rectifying K+ current. Upon reducing I Kr, the APs without EADs (no-EAD response) showed gradual prolongation of AP duration (APD), and were annihilated without AP configuration changes due to the occurrence of saddle-node bifurcations. This annihilation caused a transition to an AP with EADs as a new stable steady state. Furthermore, reducing repolarisation currents (repolarisation reserve attenuation) evoked multi-stable states consisting of APs with different APDs, and caused multiple hysteretic dynamics. Depending on initial ion circumstances within ventricular myocytes, these multi-stable AP states might increase the local/global heterogeneity of AP repolarisations in the ventricle. Thus, the EAD-induced arrhythmias with repolarisation reserve attenuation might be attributed to the APD variability caused by multi-stability in cardiac AP dynamics

Roles of Subcellular Na+ Channel Distributions in the Mechanism of Cardiac Conduction

The gap junction and voltage-gated Na+ channel play an important role in the action potential propagation. The purpose of this study was to elucidate the roles of subcellular Na+ channel distribution in action potential propagation. To achieve this, we constructed the myocardial strand model, which can calculate the current via intercellular cleft (electric-field mechanism) together with gap-junctional current (gap-junctional mechanism). We conducted simulations of action potential propagation in a myofiber model where cardiomyocytes were electrically coupled with gap junctions alone or with both the gap junctions and the electric field mechanism. Then we found that the action potential propagation was greatly affected by the subcellular distribution of Na+ channels in the presence of the electric field mechanism. The presence of Na+ channels in the lateral membrane was important to ensure the stability of propagation under conditions of reduced gap-junctional coupling. In the poorly coupled tissue with sufficient Na+ channels in the lateral membrane, the slowing of action potential propagation resulted from the periodic and intermittent dysfunction of the electric field mechanism. The changes in the subcellular Na+ channel distribution might be in part responsible for the homeostatic excitation propagation in the diseased heart