What is the clinical evidence from this study?

Study design: Other. Population: Atrial fibrillation. Intervention: Pharmacological modulation (Amiodarone, IK1 blocker, IKur blocker) vs. Control (no drug). Primary outcome: Vulnerability window to conduction block (VWCB) and re-entry (VWR).

February 25, 2014Open Access

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

Key Result

In a 3D computational model of the canine pulmonary vein, amiodarone eliminated re-entrant activity and decreased the vulnerability window to conduction block from 12 ms to 4 ms.

Structured PICO

Population

Biophysically detailed three-dimensional canine atrial model of the pulmonary veins and inter-pulmonary region of the posterior left atrium

Intervention

Pharmacological modulation with IK1 blockers, IKur blockers, or amiodarone, and simulated AF-induced electrical remodeling

Comparator

Control conditions (no remodeling, no pharmacological agents)

Outcome

Vulnerability to conduction block (VWCB) and sustained re-entry (VWR), and action potential wavelengthsurrogate

Computational modeling of canine pulmonary veins reveals that amiodarone effectively terminates re-entry and reduces wave break vulnerability by decreasing tissue heterogeneity, unlike specific potassium channel blockers which may promote wave breaks.

Limitations

Considered the pulmonary vein region only rather than the entire atria
Simple models of drug actions that did not consider drug binding kinetics or dose dependencies
Cell-to-cell coupling reduction was uniform and not linked with AF-induced increases in conduction anisotropy and levels of fibrosis
Differences between single cell and intact tissue experimental data used in the models

Abstract

AIMS: Atrial 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 RESULTS: A 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. CONCLUSION: Biophysical 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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