Elsevier

Heart Rhythm

Volume 4, Issue 12, December 2007, Pages 1553-1562
Heart Rhythm

Original-experimental
Pulmonary vein reentry—Properties and size matter: Insights from a computational analysis

https://doi.org/10.1016/j.hrthm.2007.08.017Get rights and content

Background

Pulmonary vein (PV) ablation plays an important role in atrial fibrillation (AF) therapy but suffers from a limited mechanistic understanding of PV arrhythmogenicity. Rapid focal activation has been suggested, but some evidence points to underlying reentry.

Objective

This study was performed to evaluate how the electrophysiological properties of PVs may make them a site for reentry and to analyze specifically the roles of PV dimensions and coupling properties.

Methods

A computer model designed to efficiently reproduce electrophysiological behaviors was fit to action potentials from canine left atria (LA) and PVs. To assess structural and functional arrhythmogenic determinants, an idealized PV of varying length and circumference was attached to LA tissue, and 5 seconds of activity after extrastimulation were simulated.

Results

PV reentrant activity depended critically on vein size and coupling properties. With cumulative removal of transverse and longitudinal connections, sustained (n = 23) or nonsustained (n = 93) reentries could be observed (687 simulations) for veins 1–3 cm long and 1–2 cm in circumference. The prevalence of sustained reentry increased with PV length (8% for 1 cm vs. 22% and 31% for 2 and 3 cm, respectively; P <.05 for each). The PV circumference did not affect the incidence of sustained reentry (25%, 17%, and 21% for 1-, 1.5-, and 2-cm circumferences; P = NS), but the number of reentrant events increased from 12/201 simulations for PVs with a 1-cm circumference to 48/232 and 56/254 events for PVs with 1.5- and 2-cm circumferences, respectively (P <.05). Sustained reentry cycle lengths were approximately 200–250 ms (16/23), except for the longest PVs.

Conclusion

Reentry occurs readily in PVs with realistic properties in the context of specific connection heterogeneities. Reentry properties and incidence depend on PV anisotropy and dimensions but could certainly contribute significantly to PV arrhythmogenesis.

Introduction

Unraveling the role of pulmonary veins (PVs) in atrial fibrillation (AF) remains an important goal for experimental and clinical research. Since the first note on the importance for AF initiation and maintenance,1 a large number of studies (at both the basic and clinical science levels) have been devoted to deciphering the mechanisms of PV arrhythmogenicity. Despite this effort, a precise mechanistic understanding has yet to evolve.

In line with initial clinical observations of rapid focal activity within the PVs, one experimental study found triggered arrhythmia due to delayed and early after-depolarizations along with increased pacemaker current in native PVs, which became exaggerated under conditions of tachycardia remodeling.2 Other work observed triggered activity only under specific conditions such as calcium overload or neurohumoral stimulation.3, 4 Other studies were unable to demonstrate any focal arrhythmias.5, 6, 7, 8 PV cardiomyocytes express a specific profile of ionic currents leading to shorter action potential (AP) duration (APD) in comparison with left atrial (LA) tissue.6 Impulse propagation within PVs is highly anisotropic owing to fiber arrangement (abrupt direction shifts and circumferential orientations) with reduced connexin (Cx) expression.5, 9 These observations suggested that PVs may have a substrate that is suitable for reentry and point to a possible reentrant mechanism of PV arrhythmogenicity. PV reentry is enhanced with neurohumoral stimulation with acetylcholine or isoproterenol.8, 10 Clinical observations of PV reentry have been made in small patient series.11, 12 Based on the AP and coupling properties of PV cardiomyocytes, we hypothesized that PVs may serve as a site for reentry, which may depend critically on PV size and coupling properties. To probe this possibility, we created a mathematical model that accurately reproduces the known AP properties of PV and LA cardiomyocytes and then performed in silico analysis to determine whether these properties would allow for preferential PV reentry. To vary coupling over a range of clinically relevant inhomogeneous fiber arrangement conditions, we removed longitudinal or transverse intercellular connections according to a randomization scheme.

Section snippets

Model generation and validation

Using previously reported data,6 we created a computationally efficient model of canine LA and PV myocyte APs (Figure 1). This formulation differs from more complex ionic models in that instead of reproducing as many individual currents as possible, it is designed to account for the sum of all the currents represented in three main categories: fast inward, slow inward, and slow outward currents. We have previously shown that these currents retain enough structure of the currents involved in

Results

Because of the slow and heterogeneous nature of PV propagation, discontinuous conduction could give rise to a reentrant circuit that could activate the LA. Figure 2, Figure 3 and the accompanying interactive movies (see online Supplement) depict two examples of rapid PV activity caused by circus movement reentry within the PV and driving the LA. In Figure 2, a premature atrial activation induced a PV reentrant wave that repetitively activated the LA. Heterogeneous refractoriness in the vein

Discussion

AF is a highly prevalent arrhythmia with substantial impact on morbidity, mortality, and health care costs. PV-focused interventional therapy is having a significant impact on AF burden. In the present study, we examined the role of PV properties and geometry in the generation of reentrant PV activation using a computer model.

Conclusion

The present study suggests that PV reentry in PVs can occur with realistic PV properties. PV reentry is dependent on heterogeneous and anisotropic conduction and occurs more frequently in wider veins, while it is more often sustained in longer veins. This work helps to improve our understanding of the potential mechanisms and determinants of PV arrhythmogenic activity.

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    • Cited by (0)

    This study was supported by National Institutes of Health grants nos. 5F32HL73604 (to EMC) and R01 HL075515 (to FHF), by a Deutsche Forschungsgemeinschaft grant (no. EH 201/2-1, to JRE), and by the Canadian Institutes of Health Research and the Mathematics of Information Technology and Complex Systems Network (SN). The research was facilitated by National Science Foundation grant no. MRI-0320865 and by an allocation of advanced computing resources through the support of the National Science Foundation.

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