Mechanisms of termination and prevention of atrial fibrillation by drug therapy

Workman, Antony J.; Smith, Godfrey L.; Rankin, Andrew C.

doi:10.1016/j.pharmthera.2011.02.002

Cited by 37 publications

(37 citation statements)

References 235 publications

(262 reference statements)

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“…39,40 This may explain experimental data showing that the inhibition of I Kur can actually promote the induction of AF. 41 Our simulation results may also provide mechanistic insights into the clinically observed superiority of amiodarone over other drugs used for AF treatment, 15,24,36 as amiodarone uniquely reduces the likelihood of both re-entry and wave breaks (Table 3). …”

Section: Discussionmentioning

confidence: 94%

Evolution and pharmacological modulation of the arrhythmogenic wave dynamics in canine pulmonary vein model

et al. 2014

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AimsAtrial fibrillation (AF), the commonest cardiac arrhythmia, has been strongly linked with arrhythmogenic sources near the pulmonary veins (PVs), but underlying mechanisms are not fully understood. We aim to study the generation and sustenance of wave sources in a model of the PV tissue.Methods and resultsA previously developed biophysically detailed three-dimensional canine atrial model is applied. Effects of AF-induced electrical remodelling are introduced based on published experimental data, as changes of ion channel currents (ICaL, IK1, Ito, and IKur), the action potential (AP) and cell-to-cell coupling levels. Pharmacological effects are introduced by blocking specific ion channel currents. A combination of electrical heterogeneity (AP tissue gradients of 5–12 ms) and anisotropy (conduction velocities of 0.75–1.25 and 0.21–0.31 m/s along and transverse to atrial fibres) can results in the generation of wave breaks in the PV region. However, a long wavelength (171 mm) prevents the wave breaks from developing into re-entry. Electrical remodelling leads to decreases in the AP duration, conduction velocity and wavelength (to 49 mm), such that re-entry becomes sustained. Pharmacological effects on the tissue heterogeneity and vulnerability (to wave breaks and re-entry) are quantified to show that drugs that increase the wavelength and stop re-entry (IK1 and IKur blockers) can also increase the heterogeneity (AP gradients of 26–27 ms) and the likelihood of wave breaks.ConclusionBiophysical modelling reveals large conduction block areas near the PVs, which are due to discontinuous fibre arrangement enhanced by electrical heterogeneity. Vulnerability to re-entry in such areas can be modulated by pharmacological interventions.

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Section: Discussionmentioning

confidence: 94%

Evolution and pharmacological modulation of the arrhythmogenic wave dynamics in canine pulmonary vein model

et al. 2014

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“…22 Unfortunately, as AF progresses electric remodeling of the atria render it is progressively more conducive to perpetuation of re-entry, such that the antiarrhythmic dose required to achieve sufficient action potential duration prolongation in the atria can result in proarrhythmia in the ventricles.…”

Section: Antiarrhythmic Medication For Re-entrant Rhythmsmentioning

confidence: 99%

Principles of Cardiac Electric Propagation and Their Implications for Re-entrant Arrhythmias

Spector

2013

Circ: Arrhythmia and Electrophysiology

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T he study of clinical electrophysiology essentially comprises examining how electric excitation develops and spreads through the millions of cells that constitute the heart. Given the enormous number of cells in a human heart, there is an extremely large number of possible ways that the heart can behave. We encounter rhythms across the spectrum from the organized and orderly behavior of sinus rhythm through repetitive continuous excitation (via reentry) in structurally defined circuits like atrial flutter and, finally, the complex, dynamic, and disorganized behavior of fibrillation. Despite these myriad possibilities, one can apply a basic understanding of the principles of propagation to predict how cardiac tissue will behave under varied circumstances and in response to various manipulations.In this article, we review the principles of propagation and how these can be used to understand reentry of all degrees of complexity. We use these principles to explain the mechanisms by which antiarrhythmic medications and ablation can terminate and prevent reentry. This article is not intended to be an exhaustive description of the physiology of cardiac propagation, rather, it is meant to capture the essence of propagation with sufficient detail to provide an intuitive feel for the interplay of the physiological features relevant to propagation.The figures and videos used in this article were created using a computational model of cardiac propagation (VisibleEP LLC, Colchester, VT). It is a hybrid between a physics-based and cellular automaton model. The model incorporates the fundamental features of propagation without modeling individual ion channels.1 The model manifests several relevant emergent properties, for example, electrotonic interactions, restitution of action potential duration, and conduction velocity as well as source-sink balance-dependent propagation. Impulse Propagation Cell ExcitationA cell becomes excited when the balance of inward and outward currents passes a critical point after which inward currents exceed outward and an action potential ensues. When the membrane voltage of a cell rises above the activation threshold of its depolarizing currents (sodium current [I Na + ] or calcium current [I Ca ++ ]), its inward current grows. Meanwhile, as membrane voltage increases, the amplitude of outward currents decreases. Excitation (or the lack thereof) is dependent on a delicate balance between these currents.To reach threshold, the net transmembrane current must be sufficient to discharge the membrane capacitance.2 This term is not necessarily intuitive for those unfamiliar with physics or engineering but the concept is in fact fairly simple. The membrane separates charges across the space between its inner and outer surfaces, resulting in a voltage gradient. The size of the voltage gradient is determined by the number of charges separated and the distance by which they are separated. Think of the force that is required to keep these charges from wandering away from the cell surface. This force is...

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“…The potential effectiveness of pharmacological treatment of AF was investigated in Colman et al [45]. It was demonstrated that potassium channel blockers have both pro-and anti-arrhythmic effects, compared to the multi-channel blocker amiodarone which demonstrated only anti-arrhythmic effects, consistent with experimental studies [51].…”

Section: Termination Of Atrial Fibrillationmentioning

confidence: 82%