Theory of the development of alternans in the heart during controlled diastolic interval pacing

Otani, Niels F.

doi:10.1063/1.5003250

Cited by 13 publications

(9 citation statements)

References 33 publications

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“…(2)], under constant-DI pacing, the system is unconditionally controllable, while under the other two methods, the system is conditionally controllable. The failure of constant-DI pacing in stabilizing voltage-driven instabilities agrees with the prediction by Otani 22 using a generic iterated map model. The controllability of the system depends on the strength of the memory effect and the steepness of the APD dependence on the memory variables.…”

Section: Discussionsupporting

confidence: 83%

“…Christini 17 and by Wu and Patwardhan, 18,19 called constant diastolic interval (DI) control, in which the cardiac myocyte or tissue is paced with the DI set as a constant. Recent studies [20][21][22][23] also investigated this method. In cardiac myocytes, there is a well-known property called APD restitution.…”

Section: Introductionmentioning

confidence: 99%

“…33,44 If memory suppresses APD instabilities, then it is not difficult to imagine that control may become easier in the presence of memory. However, a recent study by Otani 22 discussed the possibility of constant-DI pacing failure in controlling the voltage-driven instabilities if a steep APD dependence on the memory variable exists. As shown in a study by Sun et al, 44 the presence of memory drives alternans and more complex behaviors in AV nodal conduction.…”

Section: Introductionmentioning

confidence: 99%

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Control of voltage-driven instabilities in cardiac myocytes with memory

Landaw

2018

Chaos: An Interdisciplinary Journal of Nonlinear Science

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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.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Control of voltage-driven instabilities in cardiac myocytes with memory

Landaw

2018

Chaos: An Interdisciplinary Journal of Nonlinear Science

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“…Indeed, by controlling and maintaining a Constant DI on a beat-by-beat basis, we eliminated feedback and the inherent dependence of the DI on the preceding APD, which was successful in suppressing alternans [15, 25]. More recently though, contradictory findings demonstrating the presence of alternans in-silico during Constant DI pacing was reported by some groups [29, 30] , particularly under abnormal calcium cycling conditions. In addition, closed loop experimental validation of beat-to-beat control of alternans has exhibited limited success, especially in 2D cardiac tissue preparations [11, 24] .…”

Section: Introductionmentioning

confidence: 99%

Real-Time Closed Loop Diastolic Interval Control Prevents Cardiac Alternans in Isolated Whole Rabbit Hearts

et al. 2018

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Cardiac alternans, a beat-to-beat alternation in action potential duration (APD), can lead to fatal arrhythmias. During periodic pacing, changes in diastolic interval (DI) depend on subsequent changes in APD, thus enhancing cardiac instabilities through a 'feedback' mechanism. Recently, an anti-arrhythmic Constant DI pacing protocol was proposed and shown to be effective in suppressing alternans in 0D and 1D in silico studies. However, previous experimental validation of Constant DI pacing in the heart has been unsuccessful due to the spatio-temporal complexity of 2D cardiac tissue and the technical challenges in its real-time implementation. Here, we developed a novel closed loop system to detect T-waves from real-time ECG data, enabling successful implementation of Constant DI pacing protocol, and performed high-resolution optical mapping experiments on isolated whole rabbit hearts to validate its anti-arrhythmic effects. The results were compared with: (1) Periodic pacing (feedback inherent) and (2) pacing with heart rate variability (HRV) (feedback modulation) introduced by using either Gaussian or Physiological patterns. We observed that Constant DI pacing significantly suppressed alternans in the heart, while maintaining APD spatial dispersion and flattening the slope of the APD restitution curve, compared to traditional Periodic pacing. In addition, introduction of HRV in Periodic pacing failed to prevent cardiac alternans, and was arrhythmogenic.

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“…The bifurcations from the map model may provide mechanistic insights into slow time course or delay (or memory) induced period-doubling [23] and oscillations [8,24] shown in experiments. Differing from many previous theoretical studies [24][25][26][27][28] on the effects of memory, our iterated map model incorporates the specific feedback loops and time scales of [Ca 2+ ] i and [Na + ] i accumulation, which reveals the bifurcations leading to the complex AP dynamics in ventricular myocytes caused by feedbacks between APD and [Ca 2+ ] i and [Na + ] i . These cellular AP dynamics may play important roles in cardiac arrhythmogenesis in cardiac tissue [29].…”

Section: ) τ 2 − 4δ>0 Period-doubling Bifurcationmentioning

confidence: 99%

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

Landaw

2019

Phys. Rev. Lett.

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We develop an iterated map model to describe the bifurcations and complex dynamics caused by the feedbacks 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. In excitable cells [1], ion concentration gradients across the cell membrane are required for a negative (polarized) resting potential and excitability. The major ions are sodium ion (Na +), potassium ion (K +), and calcium ion (Ca 2+), with concentrations in the extracellular space being roughly 140 mM, 4 mM, and 1.5 mM, and in intracellular space being roughly 10 mM, 150 mM, and 100 nM, respectively. These ion gradients are primarily maintained by ion pumps, namely, the Na +-K + pump and the Na +-Ca 2+ exchange (NCX). During an action potential (AP), Na + and Ca 2+ enter the cell via voltage-gated Na + channels and Ca 2+ channels, respectively, and K + exits the cell via K + channels, which then are extruded out or brought into the cell by the pumps, maintaining ion homeostasis of the cell. Since the intracellular ion concentrations affect both ionic currents via ion channels and pumps, feedback loops form between voltage and the ion concentrations. Moreover, the ion channels and different intracellular ion concentration dynamics exhibit distinct time scales. The feedback loops and the multiple time scales can result in very interesting dynamics, such as bursting behaviors seen in many biological cells, including neurons [2-4], pancreatic β-cells [2], and cardiac cells [5-7]. Although some of the complex AP dynamics have been understood via bifurcation analyses, much work is still needed to reveal how the feedbacks and different time scales interact to give rise to these dynamics.

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Theory of the development of alternans in the heart during controlled diastolic interval pacing

Cited by 13 publications

References 33 publications

Control of voltage-driven instabilities in cardiac myocytes with memory

Control of voltage-driven instabilities in cardiac myocytes with memory

Real-Time Closed Loop Diastolic Interval Control Prevents Cardiac Alternans in Isolated Whole Rabbit Hearts

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

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