Background-Electrically based therapies for terminating atrial fibrillation (AF) currently fall into 2 categories:antitachycardia pacing and cardioversion. Antitachycardia pacing uses low-intensity pacing stimuli delivered via a single electrode and is effective for terminating slower tachycardias but is less effective for treating AF. In contrast, cardioversion uses a single high-voltage shock to terminate AF reliably, but the voltages required produce undesirable side effects, including tissue damage and pain. We propose a new method to terminate AF called far-field antifibrillation pacing, which delivers a short train of low-intensity electric pulses at the frequency of antitachycardia pacing but from field electrodes. Prior theoretical work has suggested that this approach can create a large number of activation sites ("virtual" electrodes) that emit propagating waves within the tissue without implanting physical electrodes and thereby may be more effective than point-source stimulation. Methods and Results-Using optical mapping in isolated perfused canine atrial preparations, we show that a series of pulses at low field strength (0.9 to 1.4 V/cm) is sufficient to entrain and subsequently extinguish AF with a success rate of 93% (69 of 74 trials in 8 preparations). We further demonstrate that the mechanism behind far-field antifibrillation pacing success is the generation of wave emission sites within the tissue by the applied electric field, which entrains the tissue as the field is pulsed. Conclusions-AF in our model can be terminated by far-field antifibrillation pacing with only 13% of the energy required for cardioversion. Further studies are needed to determine whether this marked reduction in energy can increase the effectiveness and safety of terminating atrial tachyarrhythmias clinically. Key Words: arrhythmia Ⅲ atrium Ⅲ cardioversion Ⅲ fibrillation Ⅲ mapping A trial fibrillation (AF) is the most common sustained cardiac arrhythmia worldwide, 1 affecting Ͼ2.2 million people in the United States alone. 2 Complications associated with chronic AF include increased risk for both thromboembolism and stroke. 2 Left untreated, paroxysmal AF often progresses to permanent AF, which is resistant to therapy. 3 Although underlying anatomic or pathophysiological factors may fuel this progression, 3 AF itself may lead to its own perpetuation through electric, structural, and metabolic remodeling of atrial tissue. The realization that AF begets AF 4 has led to management strategies that are designed to avoid the progression of AF by reducing the frequency and duration of AF episodes. Clinical Perspective on p 476One such strategy, cardioversion, attempts to reset all electric activity in the atria and requires the use of large (Ͼ5 V/cm) electric field gradients. 5-7 These high energies cause pain and trauma for the patient, damage the myocardium, and reduce battery life in implanted devices. 8 Another strategy, antitachycardia pacing (ATP), seeks to avoid the development of permanent AF by suppressing paroxysmal A...
It has been postulated that cardiac cell models accounting for changes in intracellular ion concentrations violate a conservation principle, and, as a result, computed parameters (e.g., ion concentrations and transmembrane potential, V(m)) drift in time, never attaining steady state. To address this issue, models have been proposed that invoke the charge conservation principle to calculate V(m) from ion concentrations ("algebraic" method), rather than from transmembrane current ("differential" method). The aims of this study are to compare model behavior during prolonged periods of pacing using the algebraic and differential methods, and to address the issue of model drift. We pace the Luo-Rudy dynamic model of a cardiac ventricular cell and compare the time-dependent behavior of computed parameters using the algebraic and differential methods. When ions carried by the stimulus current are taken into account, the algebraic and differential methods yield identical results and neither shows drift in computed parameters. The present study establishes the proper pacing protocol for simulation studies of cellular behavior during long periods of rapid pacing. Such studies are essential for mechanistic understanding of arrhythmogenesis, since cells are subjected to rapid periodic stimulation during many arrhythmias.
The contribution of cumulative changes in action potential duration (memory) to complex cellular electrophysiological behavior was investigated in canine cardiac Purkinje fibers. Complex behavior induced during constant pacing was caused by reciprocal interactions between the time to full repolarization (TFR), where TFR = response duration + latency, and the diastolic interval (DI). The relationship between TFR and the preceding DI during complex behavior differed from that obtained using a standard restitution protocol. In particular, higher-order periodicities and chaos were produced in fibers in which the restitution curve lacked the prerequisites for such behavior. To investigate whether shifts in the restitution curve might be expected during rapid pacing, the relationship between TFR of a test response (TFR(n + 1)) and the immediately preceding response (TFR(n)) was determined. For any fixed DI(n), reduction of TFR(n) from 240 to 130 ms was accompanied by a corresponding reduction of TFR(n + 1), whereas as TFR(n) was reduced further to 120 ms, TFR(n + 1) increased. Because of the dependence of TFR(n + 1) on TFR(n) (memory) and on the preceding DI(n) (restitution), the slope of the low-dimensional relationship between TFR(n + 1) and DI(n) at a constant pacing cycle length depended on the slopes of the restitution and memory functions. These results suggest that rapid accumulation and dissipation of memory may contribute importantly to complex electrical behavior in cardiac tissue.
Background-Dynamically induced heterogeneities of repolarization may lead to wave-front destabilizations and initiation of ventricular fibrillation (VF). In a computer modeling study, we demonstrated that specific sequences of premature stimuli maximized dynamically induced spatial dispersion of refractoriness and predisposed the heart to the development of conduction block. The purpose of this study was to determine whether the computer model results pertained to the initiation of VF in dogs in vivo. Methods and Results-Monophasic action potentials were recorded from right and left ventricular endocardium in anesthetized beagle dogs (nϭ11) in vivo. Restitution of action potential duration and conduction time and the effective refractory period after delivery of the basic stimulus (S 1 ) and each of 3 premature stimuli (S 2 , S 3 , S 4 ) were determined at baseline and during verapamil infusion. The effective refractory period data were used to determine the interstimulus intervals for a sequence of 4 premature stimuli (S 2 S 3 S 4 S 5 ϭCL VF ) for which the computer model predicted maximal spatial dispersion of refractoriness. Delivery of CL VF was associated with discordant action potential duration alternans and induction of VF in all dogs. Verapamil decreased spatial dispersion of refractoriness by reducing action potential duration and conduction time restitution in a dose-dependent fashion, effects that were associated with reduced inducibility of VF with CL VF . Conclusion-Maximizing dynamically induced spatial dispersion of repolarization appears to be an effective method for inducing VF. Reducing spatial dispersion of refractoriness by modulating restitution parameters can have an antifibrillatory effect in vivo.
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