Synchronization of chaotic early afterdepolarizations in the genesis of cardiac arrhythmias.

The synchronization of coupled oscillators plays an important role in many biological systems, including the heart. In heart diseases, cardiac myocytes can exhibit abnormal electrical oscillations, such as early afterdepolarizations (EADs), which are associated with lethal arrhythmias. A key unanswered question is how cellular EADs partially synchronize in tissue, as is required for them to propagate. Here, we present evidence, from computational simulations and experiments in isolated myocytes, that irregular EAD behavior is dynamical chaos. We then show in electrically homogeneous tissue models that chaotic EADs synchronize globally when the tissue is smaller than a critical size. However, when the tissue exceeds the critical size, electrotonic coupling can no longer globally synchronize EADs, resulting in regions of partial synchronization that shift in time and space. These regional partially synchronized EADs then form premature ventricular complexes that propagate into recovered tissue without EADs. This process creates multiple premature ventricular complexes that propagate as [corrected] "shifting" foci resembling polymorphic ventricular tachycardia. Shifting foci encountering shifting repolarization gradients can also develop localized wave breaks leading to reentry and fibrillation. As predicted by the theory, rabbit hearts exposed to oxidative stress (H(2)O(2)) exhibited multiple shifting foci causing polymorphic tachycardia and fibrillation. This mechanism explains how collective cellular behavior integrates at the tissue scale to generate lethal cardiac arrhythmias over a wide range of heart rates.

Bifurcation and chaos in a model of cardiac early afterdepolarizations.

Excitable cells can exhibit complex patterns of oscillations, such as spiking and bursting. In cardiac cells, pathological voltage oscillations, called early afterdepolarizations (EADs), have been widely observed under disease conditions, yet their dynamical mechanisms remain unknown. Here, we show that EADs are caused by Hopf and homoclinic bifurcations. During period pacing, chaos always occurs at the transition from no EAD to EADs as the stimulation frequency decreases, providing a distinct explanation for the irregular EAD behavior frequently observed in experiments.

Vulnerability to re-entry in simulated two-dimensional cardiac tissue: effects of electrical restitution and stimulation sequence.

Ventricular fibrillation is a lethal arrhythmia characterized by multiple wavelets usually starting from a single or figure-of-eight re-entrant circuit. Understanding the factors regulating vulnerability to the re-entry is essential for developing effective therapeutic strategies to prevent ventricular fibrillation. In this study, we investigated how pre-existing tissue heterogeneities and electrical restitution properties affect the initiation of re-entry by premature extrastimuli in two-dimensional cardiac tissue models. We studied two pacing protocols for inducing re-entry following the "sinus" rhythm (S1) beat: (1) a single premature (S2) extrastimulus in heterogeneous tissue; (2) two premature extrastimuli (S2 and S3) in homogeneous tissue. In the first case, the vulnerable window of re-entry is determined by the spatial dimension and extent of the heterogeneity, and is also affected by electrical restitution properties and the location of the premature stimulus. The vulnerable window first increases as the action potential duration (APD) difference between the inside and outside of the heterogeneous region increases, but then decreases as this difference increases further. Steeper APD restitution reduces the vulnerable window of re-entry. In the second case, electrical restitution plays an essential role. When APD restitution is flat, no re-entry can be induced. When APD restitution is steep, re-entry can be induced by an S3 over a range of S1S2 intervals, which is also affected by conduction velocity restitution. When APD restitution is even steeper, the vulnerable window is reduced due to collision of the spiral tips.

The pinwheel experiment revisited: effects of cellular electrophysiological properties on vulnerability to cardiac reentry.

In normal heart, ventricular fibrillation can be induced by a single properly timed strong electrical or mechanical stimulus. A mechanism first proposed by Winfree and coined the "pinwheel experiment" emphasizes the timing and strength of the stimulus in inducing figure-of-eight reentry. However, the effects of cellular electrophysiological properties on vulnerability to reentry in the pinwheel scenario have not been investigated. In this study, we extend Winfree's pinwheel experiment to show how the vulnerability to reentry is affected by the graded action potential responses induced by a strong premature stimulus, action potential duration (APD), and APD restitution in simulated monodomain homogeneous two-dimensional tissue. We find that a larger graded response, longer APD, or steeper APD restitution slope reduces the vulnerable window of reentry. Strong graded responses and long APD promote tip-tip interactions at long coupling intervals, causing the two initiated spiral wave tips to annihilate. Steep APD restitution promotes wave front-wave back interaction, causing conduction block in the central common pathway of figure-of-eight reentry. We derive an analytical treatment that shows good agreement with numerical simulation results.

Mechanism of shortened action potential duration in Na+-Ca2+ exchanger knockout mice.

In cardiac-specific Na(+)-Ca(2+) exchanger (NCX) knockout (KO) mice, the ventricular action potential (AP) is shortened. The shortening of the AP, as well as a decrease of the L-type Ca(2+) current (I(Ca)), provides a critical mechanism for the maintenance of Ca(2+) homeostasis and contractility in the absence of NCX (Pott C, Philipson KD, Goldhaber JI. Excitation-contraction coupling in Na(+)-Ca(2+) exchanger knockout mice: reduced transsarcolemmal Ca(2+) flux. Circ Res 97: 1288-1295, 2005). To investigate the mechanism that underlies the accelerated AP repolarization, we recorded the transient outward current (I(to)) in patch-clamped myocytes isolated from wild-type (WT) and NCX KO mice. Peak I(to) was increased by 78% and decay kinetics were slowed in KO vs. WT. Consistent with increased I(to), ECGs from KO mice exhibited shortened QT intervals. Expression of the I(to)-generating K(+) channel subunit Kv4.2 and the K(+) channel interacting protein was increased in KO. We used a computer model of the murine AP (Bondarenko VE, Szigeti GP, Bett GC, Kim SJ, and Rasmusson RL. Computer model of action potential of mouse ventricular myocytes. Am J Physiol Heart Circ Physiol 287: 1378-1403, 2004) to determine the relative contributions of increased I(to), reduced I(Ca), and reduced NCX current (I(NCX)) on the shape and kinetics of the AP. Reduction of I(Ca) and elimination of I(NCX) had relatively small effects on the duration of the AP in the computer model. In contrast, AP repolarization was substantially accelerated when I(to) was increased in the computer model. Thus, the increase in I(to), and not the reduction of I(Ca) or I(NCX), is likely to be the major mechanism of AP shortening in KO myocytes. The upregulation of I(to) may comprise an important regulatory mechanism to limit Ca(2+) influx via a reduction of AP duration, thus preventing Ca(2+) overload in situations of reduced myocyte Ca(2+) extrusion capacity.