Intracellular ion accumulation in the genesis of complex action potential dynamics under cardiac diseases.

Intracellular ions, including sodium (Na^{+}), calcium (Ca^{2+}), and potassium (K^{+}), etc., accumulate slowly after a change of the state of the heart, such as a change of the heart rate. The goal of this study is to understand the roles of slow ion accumulation in the genesis of cardiac memory and complex action-potential duration (APD) dynamics that can lead to lethal cardiac arrhythmias. We carry out numerical simulations of a detailed action potential model of ventricular myocytes under normal and diseased conditions, which exhibit memory effects and complex APD dynamics. We develop a low-dimensional iterated map (IM) model to describe the dynamics of Na^{+}, Ca^{2+}, and APD and use it to uncover the underlying dynamical mechanisms. The development of the IM model is informed by simulation results under the normal condition. We then use the IM model to perform linear stability analyses and computer simulations to investigate the bifurcations and complex APD dynamics, which depend on the feedback loops between APD and intracellular Ca^{2+} and Na^{+} concentrations and the steepness of the APD response to the ion concentrations. When the feedback between APD and Ca^{2+} concentration is positive, a Hopf bifurcation leading to periodic oscillatory behavior occurs as the steepness of the APD response to the ion concentrations increases. The negative feedback loop between APD and Na^{+} concentration is required for the Hopf bifurcation. When the feedback between APD and Ca^{2+} concentration is negative, period-doubling bifurcations leading to high periodicity and chaos occurs. In this case, Na^{+} accumulation plays little role in the dynamics. Finally, we carry out simulations of the detailed action potential model under two diseased conditions, which exhibit steep APD responses to ion concentrations. Under both conditions, Hopf bifurcations leading to slow oscillations or period-doubling bifurcations leading to high periodicity and chaotic APD dynamics occur, depending on the strength of the ion pump-Na^{+}-Ca^{2+} exchanger. Using functions reconstructed from the simulation data, the IM model accurately captures the bifurcations and dynamics under the two diseased conditions. In conclusion, besides using computer simulations of a detailed high-dimensional action-potential model to investigate the effects of slow ion accumulation and short-term memory on bifurcations and genesis of complex APD dynamics in cardiac myocytes under diseased conditions, this study also provides a low-dimensional mathematical tool, i.e., the IM model, to allow stability analyses for uncovering the underlying mechanisms.

The transient outward potassium current plays a key role in spiral wave breakup in ventricular tissue.

Spiral wave reentry as a mechanism of lethal ventricular arrhythmias has been widely demonstrated in animal experiments and recordings from human hearts. It has been shown that in structurally normal hearts spiral waves are unstable, breaking up into multiple wavelets via dynamical instabilities. However, many of the second-generation action potential models give rise only to stable spiral waves, raising issues regarding the underlying mechanisms of spiral wave breakup. In this study, we carried out computer simulations of two-dimensional homogeneous tissues using five ventricular action potential models. We show that the transient outward potassium current (Ito), although it is not required, plays a key role in promoting spiral wave breakup in all five models. As the maximum conductance of Ito increases, it first promotes spiral wave breakup and then stabilizes the spiral waves. In the absence of Ito, speeding up the L-type calcium kinetics can prevent spiral wave breakup, however, with the same speedup kinetics, spiral wave breakup can be promoted by increasing Ito. Increasing Ito promotes single-cell dynamical instabilities, including action potential duration alternans and chaos, and increasing Ito further suppresses these action potential dynamics. These cellular properties agree with the observation that increasing Ito first promotes spiral wave breakup and then stabilizes spiral waves in tissue. Implications of our observations to spiral wave dynamics in the real hearts and action potential model improvements are discussed.NEW & NOTEWORTHY Spiral wave breakup manifesting as multiple wavelets is a mechanism of ventricular fibrillation. It has been known that spiral wave breakup in cardiac tissue can be caused by a steeply sloped action potential duration restitution curve, a property mainly determined by the recovery of L-type calcium current. Here, we show that the transient outward potassium current (Ito) is another current that plays a key role in spiral wave breakup, that is, spiral waves can be stable for low and high maximum Ito conductance but breakup occurs for intermediate maximum Ito conductance. Since Ito is present in normal hearts of many species and required for Brugada syndrome, it may play an important role in the spiral wave stability and arrhythmogenesis under both normal condition and Brugada syndrome.

Small-conductance Ca2+-activated K+ channels promote J-wave syndrome and phase 2 reentry.

BACKGROUND: Small-conductance Ca2+-activated potassium (SK) channels play complex roles in cardiac arrhythmogenesis. SK channels colocalize with L-type Ca2+ channels, yet how this colocalization affects cardiac arrhythmogenesis is unknown. OBJECTIVE: The purpose of this study was to investigate the role of colocalization of SK channels with L-type Ca2+ channels in promoting J-wave syndrome and ventricular arrhythmias. METHODS: We carried out computer simulations of single-cell and tissue models. SK channels in the model were assigned to preferentially sense Ca2+ in the bulk cytosol, subsarcolemmal space, or junctional cleft. RESULTS: When SK channels sense Ca2+ in the bulk cytosol, the SK current (ISK) rises and decays slowly during an action potential, the action potential duration (APD) decreases as the maximum conductance increases, no complex APD dynamics and phase 2 reentry can be induced by ISK. When SK channels sense Ca2+ in the subsarcolemmal space or junctional cleft, ISK can rise and decay rapidly during an action potential in a spike-like pattern because of spiky Ca2+ transients in these compartments, which can cause spike-and-dome action potential morphology, APD alternans, J-wave elevation, and phase 2 reentry. Our results can account for the experimental finding that activation of ISK induced J-wave syndrome and phase 2 reentry in rabbit hearts. CONCLUSION: Colocalization of SK channels with L-type Ca2+ channels so that they preferentially sense Ca2+ in the subsarcolemmal or junctional space may result in a spiky ISK, which can functionally play a similar role of the transient outward K+ current in promoting J-wave syndrome and ventricular arrhythmias.

Spatially Discordant Repolarization Alternans in the Absence of Conduction Velocity Restitution.

Spatially discordant alternans (SDA) of action potential duration (APD) has been widely observed in cardiac tissue and is linked to cardiac arrhythmogenesis. Theoretical studies have shown that conduction velocity restitution (CVR) is required for the formation of SDA. However, this theory is not completely supported by experiments, indicating that other mechanisms may exist. In this study, we carried out computer simulations using mathematical models of action potentials to investigate the mechanisms of SDA in cardiac tissue. We show that when CVR is present and engaged, such as fast pacing from one side of the tissue, the spatial pattern of APD in the tissue undergoes either spatially concordant alternans or SDA, independent of initial conditions or tissue heterogeneities. When CVR is not engaged, such as simultaneous pacing of the whole tissue or under normal/slow heart rates, the spatial pattern of APD in the tissue can have multiple solutions, including spatially concordant alternans and different SDA patterns, depending on heterogeneous initial conditions or pre-existing repolarization heterogeneities. In homogeneous tissue, curved nodal lines are not stable, which either evolve into straight lines or disappear. However, in heterogeneous itssue, curved nodal lines can be stable, depending on their initial locations and shapes relative to the structure of the heterogeneity. Therefore, CVR-induced SDA and non-CVR-induced SDA exhibit different dynamical properties, which may be responsible for the different SDA properties observed in experimental studies and arrhythmogenesis in different clinical settings.

Bifurcations Caused by Feedback between Voltage and Intracellular Ion Concentrations in Ventricular Myocytes.

We develop an iterated map model to describe the bifurcations and complex dynamics caused by the feedback between voltage and intracellular Ca^{2+} and Na^{+} concentrations in paced ventricular myocytes. Voltage and Ca^{2+} can form either a positive or a negative feedback loop, while voltage and Na^{+} form a negative feedback loop. Under certain diseased conditions, when the feedback between voltage and Ca^{2+} is positive, Hopf bifurcations occur, leading to periodic oscillatory behaviors. When this feedback is negative, period-doubling bifurcation routes to alternans and chaos occur.

Control of voltage-driven instabilities in cardiac myocytes with memory.

Sudden cardiac death is known to be associated with dynamical instabilities in the heart, and thus control of dynamical instabilities is considered a potential therapeutic strategy. Different control methods were developed previously, including time-delayed feedback pacing control and constant diastolic interval pacing control. Experimental, theoretical, and simulation studies have examined the efficacy of these control methods in stabilizing action potential dynamics. In this study, we apply these control methods to control complex action potential (AP) dynamics under two diseased conditions: early repolarization syndrome and long QT syndrome, in which voltage-driven instabilities occur in the presence of short-term cardiac memory. In addition, we also develop a feedback pacing method to stabilize these instabilities. We perform theoretical analyses using iterated map models and carry out numerical simulations of AP models. We show that under the normal condition where the memory effect is minimal, all three methods can effectively control the action potential duration (APD) dynamics. Under the two diseased conditions where the memory effect is exacerbated, constant diastolic pacing control is least effective, while the feedback pacing control is most effective. Under a very strong memory effect, all three methods fail to stabilize the voltage-driven instabilities. The failure of effective control is due to memory and the all-or-none AP dynamics which results in very steep changes in APD.

Memory-induced nonlinear dynamics of excitation in cardiac diseases.

Excitable cells, such as cardiac myocytes, exhibit short-term memory, i.e., the state of the cell depends on its history of excitation. Memory can originate from slow recovery of membrane ion channels or from accumulation of intracellular ion concentrations, such as calcium ion or sodium ion concentration accumulation. Here we examine the effects of memory on excitation dynamics in cardiac myocytes under two diseased conditions, early repolarization and reduced repolarization reserve, each with memory from two different sources: slow recovery of a potassium ion channel and slow accumulation of the intracellular calcium ion concentration. We first carry out computer simulations of action potential models described by differential equations to demonstrate complex excitation dynamics, such as chaos. We then develop iterated map models that incorporate memory, which accurately capture the complex excitation dynamics and bifurcations of the action potential models. Finally, we carry out theoretical analyses of the iterated map models to reveal the underlying mechanisms of memory-induced nonlinear dynamics. Our study demonstrates that the memory effect can be unmasked or greatly exacerbated under certain diseased conditions, which promotes complex excitation dynamics, such as chaos. The iterated map models reveal that memory converts a monotonic iterated map function into a nonmonotonic one to promote the bifurcations leading to high periodicity and chaos.

Memory-Induced Chaos in Cardiac Excitation.

Excitable systems display memory, but how memory affects the excitation dynamics of such systems remains to be elucidated. Here we use computer simulation of cardiac action potential models to demonstrate that memory can cause dynamical instabilities that result in complex excitation dynamics and chaos. We develop an iterated map model that correctly describes these dynamics and show that memory converts a monotonic first return map of action potential duration into a nonmonotonic one, resulting in a period-doubling bifurcation route to chaos.

Quantitative modeling of chronic myeloid leukemia: insights from radiobiology.

Mathematical models of chronic myeloid leukemia (CML) cell population dynamics are being developed to improve CML understanding and treatment. We review such models in light of relevant findings from radiobiology, emphasizing 3 points. First, the CML models almost all assert that the latency time, from CML initiation to diagnosis, is at most ∼10 years. Meanwhile, current radiobiologic estimates, based on Japanese atomic bomb survivor data, indicate a substantially higher maximum, suggesting longer-term relapses and extra resistance mutations. Second, different CML models assume different numbers, between 400 and 10(6), of normal HSCs. Radiobiologic estimates favor values>10(6) for the number of normal cells (often assumed to be the HSCs) that are at risk for a CML-initiating BCR-ABL translocation. Moreover, there is some evidence for an HSC dead-band hypothesis, consistent with HSC numbers being very different across different healthy adults. Third, radiobiologists have found that sporadic (background, age-driven) chromosome translocation incidence increases with age during adulthood. BCR-ABL translocation incidence increasing with age would provide a hitherto underanalyzed contribution to observed background adult-onset CML incidence acceleration with age, and would cast some doubt on stage-number inferences from multistage carcinogenesis models in general.