Oscillation in Cycle Length Induces Transient Discordant and Steady-State Concordant Alternans in the Heart

Seth H Weinberg,Leslie Tung,Vladimir E Bondarenko

doi:10.1371/journal.pone.0040477

Abstract

Alternans is a beat-to-beat alternation of the cardiac action potential duration (APD) or intracellular calcium (Cai) transient. In cardiac tissue, alternans can be spatially concordant or discordant, of which the latter has been shown to increase dispersion of repolarization and promote a substrate for initiation of ventricular fibrillation. Alternans has been studied almost exclusively under constant cycle length pacing conditions. However, heart rate varies greatly on a beat-by-beat basis in normal and pathological conditions. The purpose of this study was to determine if applying a repetitive but non-constant pacing pattern, specifically cycle length oscillation (CLO), promotes or suppresses a proarrhythmic substrate. We performed computational simulations and optical mapping experiments to investigate the potential consequences of CLO. In a single cell computational model, CLO induced APD and Cai alternans, which became “phase-matched” with the applied oscillation. As a consequence of the phase-matching, in one-dimensional cable simulations, neonatal rat ventricular myocyte monolayers, and isolated adult guinea pig hearts CLO could transiently induce spatial and electromechanical discordant alternans followed by a steady-state of concordance. Our results demonstrated that under certain conditions, CLO can initiate ventricular fibrillation in the isolated hearts. On the other hand, CLO can also exert an antiarrhythmic effect by converting an existing state of discordant alternans to concordant alternans.

Highlights

Alternans is a beat-to-beat alternation of the action potential duration (APD) and/or intracellular calcium (Cai) transient amplitude
We can understand the induction of alternans during cycle length oscillation (CLO) due to APD restitution, where APD is a monotonically increasing function of the preceding diastolic interval (DI), by the following: 1. The initial step to a longer cycle length (CL) (BCL+s) prolonged the DI and subsequent APD. 2
We demonstrated that CLO can transiently promote a proarrhythmic substrate while promoting an antiarrhythmic, steady-state condition across multiple models, species, and spatial scales (Table 1)

Summary

Introduction

Alternans is a beat-to-beat alternation of the action potential duration (APD) and/or intracellular calcium (Cai) transient amplitude. At the cellular level, depending on the coupling between transmembrane voltage (Vm) and Cai, alternans can be electromechanically concordant in which long-short alternations in APD occur concurrently with large-small alternations in Cai, or electromechanically discordant in which long-short APD alternans occur concurrently with small-large Cai alternations [1]. Alternans can be spatially concordant in which longshort alternations in APD or Cai are in-phase throughout the tissue, or spatially discordant in which long-short alternations are adjacent to short-long alternations separated by a nodal line [2,3]. More recent studies have focused on the role of Cai dynamics and voltage-calcium coupling in promoting alternans [4,5]. The linkage of this oscillation to arrhythmia initiation has not been previously investigated

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