Joseph M. Starobin

Proarrhythmic Response to Potassium Channel Blockade Numerical Studies of Polymorphic Tachyarrhythmias

BACKGROUND Prompted by the results of CAST results, attention has shifted from class I agents that primarily block sodium channels to class III agents that primarily block potassium channels for pharmacological management of certain cardiac arrhythmias. Recent studies demonstrated that sodium channel blockade, while antiarrhythmic at the cellular level, was inherently proarrhythmic in the setting of a propagating wave front as a result of prolongation of the vulnerable period during which premature stimulation can initiate reentrant activation. From a theoretical perspective, sodium (depolarizing) and potassium (repolarizing) currents are complementary so that if antiarrhythmic and proarrhythmic properties are coupled to modulation of sodium currents, then antiarrhythmic and proarrhythmic properties might similarly be coupled to modulation of potassium currents. The purpose of the present study was to explore the role of repolarization currents during reentrant excitation. METHODS AND RESULTS To assess the generic role of repolarizing currents during reentry, we studied the responses of a two-dimensional array of identical excitable cells based on the FitzHugh-Nagumo model, consisting of a single excitation (sodium-like) current and a single recovery (potassium-like) current. Spiral wave reentry was initiated by use of S1S2 stimulation, with the delay timed to occur within the vulnerable period (VP). While holding the sodium conductance constant, the potassium conductance (gK) was reduced from 1.13 to 0.70 (arbitrary units), producing a prolongation of the action potential duration (APD). When gK was 1.13, the tip of the spiral wave rotated around a small, stationary, unexcited region and the computed ECG was monomorphic. As gK was reduced, the APD was prolonged and the unexcited region became mobile (nonstationary), such that the tip of the spiral wave inscribed an outline similar to a multipetaled flower; concomitantly, the computed ECG became progressively more polymorphic. The degree of polymorphism was related to the APD and the configuration of the nonstationary spiral core. CONCLUSIONS Torsadelike (polymorphic) ECGs can be derived from spiral wave reentry in a medium of identical cells. Under normal conditions, the spiral core around which a reentrant wave front rotates is stationary. As the balance of repolarizing currents becomes less outward (eg, secondary to potassium channel blockade), the APD is prolonged. When the wavelength (APD.velocity) exceeds the perimeter of the stationary unexcited core, the core will become unstable, causing spiral core drift. Large repolarizing currents shorten the APD and result in a monomorphic reentrant process (stationary core), whereas smaller currents prolong the APD and amplify spiral core instability, resulting in a polymorphic process. We conclude that, similar to sodium channel blockade, the proarrhythmic potential of potassium channel blockade in the setting of propagation may be directly linked to its cellular antiarrhythmic potential, ie, arrhythmia suppression resulting from a prolonged APD may, on initiation of a reentrant wave front, destabilize the core of a rotating spiral, resulting in complex motion (precession) of the spiral tip around a nonstationary region of unexcited cells. In tissue with inhomogeneities, core instability alters the activation sequence from one reentry cycle to the next and can lead to spiral wave fractination as the wave front collides with inhomogeneous regions. Depending on the nature of the inhomogeneities, wave front fragments may annihilate one another, producing a nonsustained arrhythmia, or may spawn new spirals (multiple wavelets), producing fibrillation and sudden cardiac death.

Late Na channels in cardiac cells: the physiological role of background Na channels

Two types of the late Na channels, burst and background, were studied in Purkinje and ventricular cells. In the whole-cell configuration, steady-state Na currents were recorded at potentials (-70 to -80 mV) close to the normal cell resting potential. The question of the contribution of late Na channels to this background Na conductance was investigated. During depolarization, burst Na channels were active for periods (up to approximately 5 s), which exceeded the action potential duration. However, they eventually closed without reopening, indicating the presence of slow and complete inactivation. When, at the moment of burst channel opening, the potential was switched to -80 mV, the channel closed quickly without reopening. We conclude that the burst Na channels cannot contribute significantly to the background Na conductance. Background Na channels undergo incomplete inactivation. After a step depolarization, their activity decreased in time, approaching a steady-state level. Background Na channel openings could be recorded at constant potentials in the range from -120 to 0 mV. After step depolarizations to potentials near -70 mV and more negative, a significant fraction of Na current was carried by the background Na channels. Analysis of the background channel behavior revealed that their gating properties are qualitatively different from those of the early Na channels. We suggest that background Na channels represent a special type of Na channel that can play an important role in the initiation of cardiac action potential and in the TTX-sensitive background Na conductance.

Vulnerability in one-dimensional excitable media

Abstract Potentially life-threatening cardiac arrhythmias can be iniated with stimuli timed to occur during the “vulnerable window (VW)”. We defined VW as the time interval between the “conditioning” and “test” stimuli following in sequence, during which the test stimulus response propagates in only one direction. We show that the VW is a generic feature of excitable media and describe the relationship between the properties of an excitable medium and the VW. We present asymptotic results that reveal the sensitivity of the VW to both the propagation velocity of the conditioning wavefront and the recovery process parameters. We also have identified a critical length of medium that must be excited in order to reveal vulnerability. Analytical results are in agreement with numerical studies.

The role of a critical excitation length scale in dynamics of reentrant cardiac arrhythmias

Summary We discuss computer simulations of one- and two-dimensional excitation waves corresponding to normal and abnormal rhythms in a model of myocardium. Our studies are aimed at finding the major physiologic parameters governing such transient processes as the formation of a reentrant wave and its subsequent degradation into the malignant cardiac arrhythmia – ventricular fibrillation. Our results demonstrate that in both the one- and two-dimensional cases the stability of a periodic process (representing a regular or VT rhythm) is determined by the same two physiologic parameters: the wavewidth , which is approximately is the width of depolarized zone, and ratio of to the critical length , which is defined as the wavewidth of an action potential propagating with the minimum possible speed. The amazing feature of general excitable medium is that these two numbers play predominate role in determining the behavior of the system. The parameter determines the length scale (size) of an ectopic region that may initiate a wave. It also determines the duration of the vulnerable window for initiating the unidirectional block as well as a minimum permissible length of the reentrant circuit. In two dimensions the relation between the diameter of the spiral core and the value of determines the pattern of spiral tip motion (near circular versus meandering) as it represents the outcome of the balance between electrical sources from depolarizing membrane and the electrical sinks (diffusive, i.e. Ohmic fluxes). This balance controls in a similar way two important electrophysiologic processes, the separation of a spiral tip from unexcitable obstacle (scar tissue) and the transition to meandering of the spiral tip in the homogeneous 2D medium. We also present some evidence that depending on the value of the waveforms of the simulated ECGs for reentrant activity vary from monomorphic to polymorphic.

Bursting Regimes in a Reaction-Diffusion System with Action Potential-Dependent Equilibrium

The equilibrium Nernst potential plays a critical role in neural cell dynamics. A common approximation used in studying electrical dynamics of excitable cells is that the ionic concentrations inside and outside the cell membranes act as charge reservoirs and remain effectively constant during excitation events. Research into brain electrical activity suggests that relaxing this assumption may provide a better understanding of normal and pathophysiological functioning of the brain. In this paper we explore time-dependent ionic concentrations by allowing the ion-specific Nernst potentials to vary with developing transmembrane potential. As a specific implementation, we incorporate the potential-dependent Nernst shift into a one-dimensional Morris-Lecar reaction-diffusion model. Our main findings result from a region in parameter space where self-sustaining oscillations occur without external forcing. Studying the system close to the bifurcation boundary, we explore the vulnerability of the system with respect to external stimulations which disrupt these oscillations and send the system to a stable equilibrium. We also present results for an extended, one-dimensional cable of excitable tissue tuned to this parameter regime and stimulated, giving rise to complex spatiotemporal pattern formation. Potential applications to the emergence of neuronal bursting in similar two-variable systems and to pathophysiological seizure-like activity are discussed.

Critical scale of propagation influences dynamics of waves in a model of excitable medium

Background Duration and speed of propagation of the pulse are essential factors for stability of excitation waves. We explore the propagation of excitation waves resulting from periodic stimulation of an excitable cable to determine the minimal stable pulse duration in a rate-dependent modification of a Chernyak-Starobin-Cohen reaction-diffusion model. Results Various pacing rate dependent features of wave propagation were studied computationally and analytically. We demonstrated that the complexity of responses to stimulation and evolution of these responses from stable propagation to propagation block and alternans was determined by the proximity between the minimal level of the recovery variable and the critical excitation threshold for a stable solitary pulse. Conclusion These results suggest that critical propagation of excitation waves determines conditions for transition to unstable rhythms in a way similar to unstable cardiac rhythms. Established conditions were suitably accurate regardless of rate dependent features and the magnitude of the slopes of restitution curves.

AN EASY METHOD TO SYNTHESIZE CARBON-COATED QUANTUM DOTS

This manuscript describes a general and simple method to carbon-coat quantum dots (QDs) using microwave-assisted technology. By coating QDs with carbohydrates, you extend their application for bioimaging (in vitro and in vivo) as the metal core is now shielded by a protective coating layer. XRD and TEM verified that nanoparticles were coated with a layer of carbon-based material (reduced sucrose). In addition, we demonstrated the versatility of this approach by coating other types of nanoparticles (i.e. gold). UV–Visible spectroscopic analysis presented a red shift in absorbance after carbon coating which further confirmed that the surface of these nanoparticles was modified. QDs emission wavelength was not altered but experienced an increase in intensity. The carbon-coated QDs and gold nanoparticles generated in this study measured 14 nm and 60 nm, respectively.

Entrainment of marginally stable excitation waves by spatially extended sub-threshold periodic forcing

We introduce a novel approach of stabilizing the dynamics of excitation waves by spatially extended sub-threshold periodic forcing. Entrainment of unstable primary waves has been studied numerically for different amplitudes and frequencies of additional sub-threshold stimuli. We determined entrainment regimes under which excitation blocks were transformed into consistent 1:1 responses. These responses were spatially homogeneous and synchronized in the entire excitable medium. Compared to primary pulses, pulses entrained by secondary stimulations were stable at considerably shorter periods which decreased at higher amplitudes and greater number of secondary stimuli. Our results suggest a practical methodology for stabilization of excitation in reaction-diffusion media such as nerve tissue with regions of reduced excitability.

Spiral wave meandering, wavefront-obstacle separation and cardiac arrhythmias

Spiral wave tips rotate either around a circular core or meander, inscribing a non-circular pattern. The transition to meandering was found to be equivalent to the transition from wave tip separation to wave tip attachment around the end of an unexcitable strip of thickness comparable to the wavefront thickness. The medium properties defining the transition from circular to non-circular spiral tip movement is accurately predicted by the balance of the diffusive fluxes in the vicinity of the wave tip within the boundary layer of the order of the wavefront thickness. Small changes in the boundary layer charge can dramatically alter spiral tip motion and provide a new tool for control and classification of cardiac arrhythmias.

Cardiac and gait rhythms in healthy younger and older adults during treadmill walking tasks

BackgroundAging and pathology result in changes in the dynamics of several physiological subsystems. Often, these changes are concurrent, altering the dynamics between subsystems. Cardiac and gait rhythms are one example in which patterns change during physical activity.AimsThe purpose of this research is to simultaneously monitor changes in cardiac and gait rhythms when participants complete various treadmill walking tasks—normal speed, fast speed, and while synchronizing steps with a blinking metronome.MethodsThe cardiac and gait rhythms of younger and older healthy adults were examined in this study during treadmill walking tasks. Pre-test and post-test walking at a preferred walking speed were compared to fast walking and walking with a gait synchronization test. Cardiac and gait rhythms were observed to calculate the mean, standard deviation, coefficient of variation, detrended fluctuation analysis scaling exponent alpha (DFA α), and sample entropy from each 15-min trial. Separate MANOVAs were used to examine the two experimental conditions for cardiac and gait rhythm variability.ResultsDuring the gait synchronization experiment, main effects for phase were exhibited for all gait variables, but none were shown during the fast walking task. Meanwhile, the cardiac rhythms demonstrated decreased mean and increased DFA α only during the synchronization condition.DiscussionParticipants, regardless of age, exhibited similar patterns of change in their cardiac and locomotor rhythms during the treadmill walking tasks. Cardiac rhythms were only altered during the gait synchronization task, suggesting it may be possible to simultaneously influence the variability and structure of cardiac and gait rhythms.