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Initiation of reentry requires 2 factors: (1) a triggering event, most commonly focal excitations such as premature ventricular complexes (PVCs); and (2) a vulnerable substrate with regional dispersion of refractoriness and/or excitability, such as occurs during the T wave of the electrocardiogram when some areas of the ventricle have repolarized and recovered excitability but others have not. When the R wave of a PVC coincides in time with the T wave of the previous beat, this timing can lead to unidirectional block and initiation of reentry, known as the R-on-T phenomenon. Classically, the PVC triggering reentry has been viewed as arising focally from 1 region and propagating into another region whose recovery is delayed, resulting in unidirectional conduction block and reentry initiation. However, more recent evidence indicates that PVCs also can arise from the T wave itself. In the latter case, the PVC initiating reentry is not a separate event from the T wave but rather is causally generated from the repolarization gradient that manifests as the T wave. We call the former an R-to-T mechanism and the latter an R-from-T mechanism, which are initiation mechanisms distinct from each other. Both are important components of the R-on-T phenomenon and need to be taken into account when designing antiarrhythmic strategies. Strategies targeting suppression of triggers alone or vulnerable substrate alone may be appropriate in some instances but not in others. Preventing R-from-T arrhythmias requires suppressing the underlying dynamic tissue instabilities responsible for producing both triggers and substrate vulnerability simultaneously. The same principles are likely to apply to supraventricular arrhythmias.

BackgroundDelayed afterdepolarizations (DADs) have been well characterized as arrhythmia triggers, but their role in generating a tissue substrate vulnerable to reentry is not well understood.ObjectiveThe purpose of this study was to test the hypothesis that random DADs can self-organize to generate both an arrhythmia trigger and a vulnerable substrate simultaneously in cardiac tissue as a result of gap junction coupling.MethodsComputer simulations in 1-dimensional cable and 2-dimensional tissue models were performed. The cellular DAD amplitude was varied by changing the strength of sarcoplasmic reticulum calcium release. Random DAD latency and amplitude in different cells were simulated using gaussian distributions.ResultsDepending on the strength of spontaneous sarcoplasmic reticulum calcium release and other conditions, random DADs in cardiac tissue resulted in the following behaviors: (1) triggered activity (TA); (2) a vulnerable tissue substrate causing unidirectional conduction block and reentry by inactivating sodium channels; (3) both triggers and a vulnerable substrate simultaneously by generating TA in regions next to regions with subthreshold DADs susceptible to unidirectional conduction block and reentry. The probability of the latter 2 behaviors was enhanced by reduced sodium channel availability, reduced gap junction coupling, increased tissue heterogeneity, and less synchronous DAD latency.ConclusionDADs can self-organize in tissue to generate arrhythmia triggers, a vulnerable tissue substrate, and both simultaneously. Reduced sodium channel availability and gap junction coupling potentiate this mechanism of arrhythmias, which are relevant to a variety of heart disease conditions.

Background: In normal atrial and ventricular tissue, the electrical wavefronts are mediated by the fast sodium current (I(Na)), whereas in sinoatrial and atrioventricular nodal tissue, conduction is mediated by the slow L-type calcium current (I(Ca,L)). However, it has not been shown whether the same tissue can exhibit both the I(Na)-mediated and the I(Ca,L)-mediated conduction.Objective: This study sought to test the hypothesis that bi-stable cardiac wave conduction, mediated by I(Na) and I(Ca,L), respectively, can occur in the same tissue under conditions promoting early afterdepolarizations (EADs), and to study how this novel wave dynamics is related to the mechanisms of EAD-mediated arrhythmias.Methods: Computer models of two-dimensional (2D) tissue with a physiologically detailed action potential model were used to study the bi-stable wave dynamics. Theoretical predictions were tested experimentally by optical mapping in neonatal rat ventricular myocyte monolayers.Results: In the same 2D homogeneous tissue, we could induce spiral waves that are mediated by either I(Na) or I(Ca,L) under conditions in which the action potential model exhibited EADs. This bi-stable wave propagation behavior was similar to bi-stability shown in many other nonlinear systems. Because the bi-stable states are also excitable, we call this novel behavior bi-excitability. In a 2D heterogeneous tissue, the I(Ca,L)-mediated spiral wave meanders, giving rise to a twisting electrocardiographic QRS axis, resembling torsades de pointes, whereas the coexistence and interplay between the I(Na)-mediated wavefronts and I(Ca,L)-mediated wavefronts give rise to polymorphic ventricular tachycardia. We also present experimental evidence for bi-excitability under EAD-promoting conditions in neonatal rat ventricular myocyte monolayers exposed to BayK8644 and isoproterenol.Conclusion: Under EAD-prone conditions, both I(Na)-mediated conduction and I(Ca,L)-mediated conduction can occur in the same tissue. These novel wave dynamics may be responsible for certain EAD-mediated arrhythmias, such as torsades de pointes and polymorphic ventricular tachycardia. [ABSTRACT FROM AUTHOR]

Background: Bidirectional ventricular tachycardia (BVT), which is characterized by an alternating beat-to-beat ECG QRS axis, is a rare but intriguing arrhythmia associated with digitalis toxicity, familial catecholaminergic polymorphic ventricular tachycardia (CPVT), and several other conditions that predispose cardiac myocytes to delayed afterdepolarizations (DADs) and triggered activity. Evidence from human and animal studies attributes BVT to alternating ectopic foci originating from the distal His-Purkinje system in the left and/or right ventricle, respectively.Objective: The purpose of this study was to evaluate a simple "ping pong" model of reciprocating bigeminy to explain BVT.Methods: We constructed a two-dimensional anatomic model of the rabbit ventricles with a simplified His-Purkinje system, in which different sites in the His-Purkinje system had different heart rate thresholds for DAD-induced bigeminy.Results: When the heart rate exceeded the threshold for bigeminy at the first site in the His-Purkinje system, ventricular bigeminy developed, causing the heart rate to accelerate and exceed the threshold for bigeminy at the second site. Thus, the triggered beat from the first site induced a triggered beat from the second site. The triggered beat from the second site next reciprocated by inducing a triggered beat from the first site, and so forth. Bigeminy from two sites produced BVT, and that from three or more sites produced polymorphic VT.Conclusion: This "ping pong" mechanism of reciprocating bigeminy readily produces the characteristic ECG pattern of BVT and its degeneration to polymorphic VT if additional sites develop bigeminy. [ABSTRACT FROM AUTHOR]

Background: Under conditions promoting early afterdepolarizations (EADs), ventricular tissue can become bi-excitable, that is, capable of wave propagation mediated by either the Na current (INa) or the L-type calcium current (ICa,L), raising the possibility that ICa,L-mediated reentry may contribute to polymorphic ventricular tachycardia (PVT) and torsades de pointes. ATP-sensitive K current (IKATP) activation suppresses EADs, but the effects on ICa,L-mediated reentry are unknown. Objective: To investigate the effects of IKATP activation on ICa,L-mediated reentry. Methods: We performed optical voltage mapping in cultured neonatal rat ventricular myocyte monolayers exposed to BayK8644 and isoproterenol. The effects of pharmacologically activating IKATP with pinacidil were analyzed. Results: In 13 monolayers with anatomic ICa,L-mediated reentry around a central obstacle, pinacidil (50 μM) converted ICa,L-mediated reentry to INa-mediated reentry. In 33 monolayers with functional ICa,L-mediated reentry (spiral waves), pinacidil terminated reentry in 17, converted reentry into more complex INa-mediated reentry resembling fibrillation in 12, and had no effect in 4. In simulated 2-dimensional bi-excitable tissue in which ICa,L- and INa-mediated wave fronts coexisted, slow IKATP activation (over minutes) reliably terminated rotors but rapid IKATP activation (over seconds) often converted ICa,L-mediated reentry to INa-mediated reentry resembling fibrillation. Conclusions: IKATP activation can have proarrhythmic effects on EAD-mediated arrhythmias if ICa,L-mediated reentry is present. [ABSTRACT FROM AUTHOR]

Early afterdepolarizations (EADs) are an important cause of lethal ventricular arrhythmias in long QT syndromes and heart failure, but the mechanisms by which EADs at the cellular scale cause arrhythmias such as polymorphic ventricular tachycardia (PVT) and torsades de pointes (TdP) at the tissue scale are not well understood. Here we summarize recent progress in this area, discussing (1) the ionic basis of EADs, (2) evidence that deterministic chaos underlies the irregular behavior of EADs, (3) mechanisms by which chaotic EADs synchronize in large numbers of coupled cells in tissue to overcome source–sink mismatches, (4) how this synchronization process allows EADs to initiate triggers and generate mixed focal reentrant ventricular arrhythmias underlying PVT and TdP, and (5) therapeutic implications. [ABSTRACT FROM AUTHOR]

Background: Recent experimental studies have documented that functional gap junctions form between fibroblasts and myocytes, raising the possibility that fibroblasts play roles in cardiac electrophysiology that extend beyond acting as passive electrical insulators. Objective: The purpose of this study was to use computational models to investigate how fibroblasts may affect cardiac conduction and vulnerability to reentry under different fibroblast-myocyte coupling conditions and tissue structures. Methods: Computational models of two-dimensional tissue with fibroblast-myocyte coupling were developed and numerically simulated. Myocytes were modeled by the phase I of the Luo-Rudy model, and fibroblasts were modeled by a passive model. Results: Besides slowing conduction by cardiomyocyte decoupling and electrotonic loading, fibroblast coupling to myocytes elevates myocyte resting membrane potential, causing conduction velocity to first increase and then decrease as fibroblast content increases, until conduction failure occurs. Fibroblast-myocyte coupling can also enhance conduction by connecting uncoupled myocytes. These competing effects of fibroblasts on conduction give rise to different conduction patterns under different fibroblast-myocyte coupling conditions and tissue structures. Elevation of myocyte resting potential due to fibroblast-myocyte coupling slows sodium channel recovery, which extends postrepolarization refractoriness. Owing to this prolongation of the myocyte refractory period, reentry was more readily induced by a premature stimulation in heterogeneous tissue models when fibroblasts were electrotonically coupled to myocytes compared with uncoupled fibroblasts acting as pure passive electrical insulators. Conclusions: Fibroblasts affect cardiac conduction by acting as obstacles or by creating electrotonic loading and elevating myocyte resting potential. Functional fibroblast-myocyte coupling prolongs the myocyte refractory period, which may facilitate induction of reentry in cardiac tissue with fibrosis. [Copyright &y& Elsevier]