James N. Weiss

Mechanisms of discordant alternans and induction of reentry in simulated cardiac tissue.

BackgroundT-wave alternans, which is associated with the genesis of cardiac fibrillation, has recently been related to discordant action potential duration (APD) alternans. However, the cellular electrophysiological mechanisms responsible for discordant alternans are poorly understood. Methods and ResultsWe simulated a 2D sheet of cardiac tissue using phase 1 of the Luo-Rudy cardiac action potential model. A steep (slope >1) APD restitution curve promoted concordant APD alternans and T-wave alternans without QRS alternans. When pacing was from a single site, discordant APD alternans occurred only when the pacing rate was fast enough to engage conduction velocity (CV) restitution, producing both QRS and T-wave alternans. Tissue heterogeneity was not required for this effect. Discordant alternans markedly increases dispersion of refractoriness and increases the ability of a premature stimulus to cause localized wavebreak and induce reentry. In the absence of steep APD restitution and of CV restitution, sustained discordant alternans did not occur, but reentry could be induced if there was marked electrophysiological heterogeneity. Both discordant APD alternans and preexisting APD heterogeneity facilitate reentry by causing the waveback to propagate slowly. ConclusionDiscordant alternans arises dynamically from APD and CV restitution properties and markedly increases dispersion of refractoriness. Preexisting and dynamically induced (via restitution) dispersion of refractoriness independently increase vulnerability to reentrant arrhythmias. Reduction of dynamically induced dispersion by appropriate alteration of electrical restitution has promise as an antiarrhythmic strategy.

Chaos and the Transition to Ventricular Fibrillation: A New Approach to Antiarrhythmic Drug Evaluation

Sudden cardiac death resulting from ventricular fibrillation can be separated into 2 components: initiation of tachycardia and degeneration of tachycardia to fibrillation. Clinical drug studies such as CAST and SWORD demonstrated that focusing exclusively on the first component is inadequate as a therapeutic modality. The hope for developing effective pharmacological therapy rests on a comprehensive understanding of the second component, the transition from tachycardia to fibrillation. We summarize evidence that the transition from tachycardia to fibrillation is a transition to spatiotemporal chaos, with similarities to the quasiperiodic transition to chaos seen in fluid turbulence. In this scenario, chaos results from the interaction of multiple causally independent oscillatory motions. Simulations in 2-dimensional cardiac tissue suggest that the destabilizing oscillatory motions during spiral-wave reentry arise from restitution properties of action potential duration and conduction velocity. The process of spiral-wave breakup in simulated cardiac tissue predicts remarkably well the sequence by which tachycardia degenerates to fibrillation in real cardiac tissue. Modifying action potential duration and conduction velocity restitution characteristics can prevent spiral-wave breakup in simulated cardiac tissue, suggesting that drugs with similar effects in real cardiac tissue may have antifibrillatory efficacy (the Restitution Hypothesis). If valid for the real heart, the Restitution Hypothesis will support a new paradigm for antiarrhythmic drug classification, incorporating an antifibrillatory profile based on effects on cardiac restitution and the traditional antitachycardia profile (classes 1 through 4).

Spatiotemporal Heterogeneity in the Induction of Ventricular Fibrillation by Rapid Pacing Importance of Cardiac Restitution Properties

The mechanism by which rapid pacing induces ventricular fibrillation (VF) is unclear. We performed computerized epicardial mapping studies in 10 dogs, using 19-beat pacing trains. The pacing interval (PI) of the first train was 300 ms and then was progressively shortened until VF was induced. For each PI, we constructed restitution curves for the effective refractory period (ERP). When the PI was long, the activation cycle length (CL) was constant throughout the mapped region. However, as the PI shortened, there was an increase in the spatiotemporal complexity of the CL variations and an increase in the slope of the ERP restitution curve. In 5 dogs, we documented the initiation of VF by wavebreak at the site of long-short CL variations. Computer simulation studies using the Luo-Rudy I ventricular action potential model in simulated 2-dimensional tissue reproduced the experimental results when normal ERP and conduction velocity (CV) restitution properties were intact. By altering CV and ERP restitutions in this model, we found that CV restitution creates spatial CL variations, whereas ERP restitution underlies temporal, beat-to-beat variations in refractoriness during rapid pacing. Together, the interaction of CV and ERP restitutions produces spatiotemporal oscillations in cardiac activation that increase in amplitude as the PI decreases, ultimately causing wavebreak at the site of intrinsic heterogeneity. This initial wavebreak then leads to the formation of spiral waves and VF. These findings support a key role for both CV and ERP restitutions in the initiation of VF by rapid pacing.

Ventricular Fibrillation How Do We Stop the Waves From Breaking

Abstract— Combined experimental and theoretical developments have demonstrated that in addition to preexisting electrophysiological heterogeneities, cardiac electrical restitution properties contribute to breakup of reentrant wavefronts during cardiac fibrillation. Developing therapies that favorably alter electrical restitution properties have promise as a new paradigm for preventing fibrillation.

Electrical restitution and cardiac fibrillation.

Restitution and Fibrillation. Combined experimental and theoretical work has shown that restitution properties of the cardiac action potential duration and conduction velocity contribute to breakup of reentrant wavefronts during cardiac fibrillation independent of preexisting electrophysiologic heterogeneities in the tissue. Developing therapies that favorably alter these cardiac electrical restitution properties are a promising new approach to preventing fibrillation.

Mechanism of Acceleration of Functional Reentry in the Ventricle Effects of ATP-Sensitive Potassium Channel Opener

BACKGROUND The effect of effective refractory period (ERP) shortening on the vulnerability and characteristics of induced functional reentry in the ventricle remain poorly defined. We hypothesized that ERP shortening increases ventricular vulnerability to reentry and accelerates its rate, as is the case in the atrium. METHODS AND RESULTS The epicardial surfaces of 19 isolated and superfused canine right ventricular slices (4x4 cm and <2 mm thick) were mapped with 480 bipolar electrodes 1.6 mm apart. Vulnerability was tested during pacing at a cycle length (CL) of 600 ms and with a single premature stimulus of 5-ms duration at increasing current strength of 1 to 100 mA. Cromakalim (10 micromol/L), an ATP-sensitive potassium channel opener, caused a significant (P<0. 001) shortening of the ERP but had no effect on conduction velocity. Cromakalim increased (P<0.01) the vulnerability (product of current and the stimulus coupling interval) for reentry induction. Reentry had a significantly shorter CL and lasted for a longer duration (P<0. 001). The central core around which the wave front rotated became smaller, which caused shortening of the CL of reentry. A significant (P<0.001) linear correlation was found between core size and reentry CL. These effects of cromakalim were reversible. Two-dimensional simulation studies using the modified Luo-Rudy I model of cardiac action potential, in which the refractory period was variably shortened by a progressive increase of the time-independent potassium conductance, reproduced the experimental findings. CONCLUSIONS ERP shortening by an ATP-sensitive potassium channel opener increases ventricular vulnerability to reentry and accelerates its rate by decreasing the core size around which the wave front rotates.

Importance of location and timing of electrical stimuli in terminating sustained functional reentry in isolated swine ventricular tissues: Evidence in support of a small reentrant circuit

BACKGROUND In excitable chemical media, a spiral wave is formed by reentrant excitation around a core and normal propagation away from the core. Whether or not this applies to cardiac muscle is unknown. METHODS AND RESULTS In six isolated swine ventricular slices, we induced sustained episodes of functional reentry with a stationary core. A train of stimuli applied away from the core (7- to 8-mm distance) and near the core (within 1.6 mm) terminated 5 of 24 and 14 of 17 episodes of reentry, respectively (P<.001). When the stimulus was applied away from the core, successful terminations occurred when the line connecting the stimulus and the core was along the myocardial fiber orientation and when the coupling interval was 54+/-11% of the reentrant cycle length. Stimulation near the core terminated reentry primarily by propagation of the stimulus-induced wave fronts that closed up the excitable gap. However, in two episodes, the application of a stimulus near the core changed the electrogram morphology in only four bipolar pairs. This was sufficient to cause abrupt termination of reentry. CONCLUSIONS (1) A thin layer of activation near the core is responsible for the maintenance of functional reentry. (2) Access to the tissue near the core is essential for the termination of functional reentry by a point stimulus. (3) To terminate reentry with a stimulus away from the core, the stimulus must occur at certain critical coupling intervals, and the line connecting the stimulus and the core must be roughly parallel to the fiber orientation.

Spirals, chaos, and new mechanisms of wave propagation

The chaos theory is based on the idea that phenomena that appear disordered and random may actually be produced by relatively simple deterministic mechanisms. The disordered (aperiodic) activation that characterizes a chaotic motion is reached through one of a few well‐defined paths that are characteristic of nonlinear dynamical systems. Our group has been studying VF using computerized mapping techniques. We found that in electrically induced VF, reentrant wavefronts (spiral waves) are present both in the initial tachysystolic stage (resembling VT) and the later tremulous incoordination stage (true VF). The electrophysiological characteristics associated with the transition from VT to VF is compatible with the quasiperiodic route to chaos as described in the Ruelle‐Takens theorem. We propose that specific restitution of action potential duration (APD) and conduction velocity properties can cause a spiral wave (the primary oscillator) to develop additional oscillatory modes that lead to spiral meander and breakup. When spiral waves begin to meander and are modulated by other oscillatory processes, the periodic activity is replaced by unstable quasiperiodic oscillation, which then undergoes transition to chaos, signaling the onset of VF. We conclude that VF is a form of deterministic chaos. The development of VF is compatible with quasiperiodic transition to chaos. These results indicate that both the prediction and the control of fibrillation are possible based on the chaos theory and with the advent of chaos control algorithms.

Mechanisms of Ventricular Fibrillation Induction by 60-Hz Alternating Current in Isolated Swine Right Ventricle

BackgroundThe mechanisms by which 60-Hz alternating current (AC) can induce ventricular fibrillation (VF) are unknown. Methods and ResultsWe studied 7 isolated perfused swine right ventricles in vitro. The action potential duration restitution curve was determined. Optical mapping techniques were used to determine the patterns of activation on the epicardium during 5-second 60-Hz AC stimulation (10 to 999 &mgr;A). AC captured the right ventricles at 100±65 &mgr;A, which is significantly lower than the direct current pacing threshold (0.77±0.45 mA, P <0.05). AC induced ventricular tachycardia or VF at 477±266 &mgr;A, when the stimulated responses to AC had (1) short activation CLs (128±14 ms), (2) short diastolic intervals (16±9 ms), and (3) short diastolic intervals associated with a steep action potential duration restitution curve. Optical mapping studies showed that during rapid ventricular stimulation by AC, a wave front might encounter the refractory tail of an earlier wave front, resulting in the formation of a wave break and VF. Computer simulations reproduced these results. ConclusionsAC at strengths less than the regular pacing threshold can capture the ventricle at fast rates. Accidental AC leak to the ventricles could precipitate VF and sudden death if AC results in a fast ventricular rate coupled with a steep restitution curve and a nonuniform recovery of excitability of the myocardium.