Discordant Alternans as a Mechanism for Initiation of Ventricular Fibrillation In Vitro

Abstract

BackgroundVentricular tachyarrhythmias are often preceded by short sequences of premature ventricular complexes. In a previous study, a restitution‐based computational model predicted which sequences of stimulated premature complexes were most likely to induce ventricular fibrillation in canines in vivo. However, the underlying mechanism, based on discordant‐alternans dynamics, could not be verified in that study. The current study seeks to elucidate the mechanism by determining whether the spatiotemporal evolution of action potentials and initiation of ventricular fibrillation in in vitro experiments are consistent with model predictions.Methods and ResultsOptical mapping voltage signals from canine right‐ventricular tissue (n=9) were obtained simultaneously from the entire epicardium and endocardium during and after premature stimulus sequences. Model predictions of action potential propagation along a 1‐dimensional cable were developed using action potential duration versus diastolic interval data. The model predicted sign‐change patterns in action potential duration and diastolic interval spatial gradients with posterior probabilities of 91.1%, and 82.1%, respectively. The model predicted conduction block with 64% sensitivity and 100% specificity. A generalized estimating equation logistic‐regression approach showed that model‐prediction effects were significant for both conduction block (P<1×10−15, coefficient 44.36) and sustained ventricular fibrillation (P=0.0046, coefficient, 1.63) events.ConclusionsThe observed sign‐change patterns favored discordant alternans, and the model successfully identified sequences of premature stimuli that induced conduction block. This suggests that the relatively simple discordant‐alternans‐based process that led to block in the model may often be responsible for ventricular fibrillation onset when preceded by premature beats. These observations may aid in developing improved methods for anticipating block and ventricular fibrillation.

Mechanism of Ventricular Fibrillation: Current Status and Problems

“…A restitution-based computational model predicted which sequences of stimulated premature complexes were most likely to induce VF [13]. Alternance mechanism for VF initiation in vitro was evaluated, and the model identi ed sequences of premature stimuli that induced a conduction block, which created a rotor [14]. The relatively simple discordant-alternance-based process that led to blockade in the model may often be responsible for VF onset (Fig.…”

Electrophysiological Mechanisms Underlying T-Wave Alternans and Their Role in Arrhythmogenesis

“…At the tissue level, cellular AP alternans can be reflected as spatially concordant alternans (SCA), where the whole tissue exhibits action potential duration (APD) alternans of in-phase changes. It may also be reflected as spatially discordant alternans (SDA), in which the APD in different regions exhibit APD alternans of out-of-phase changes or otherwise offset (higher period) phase ( Munoz et al, 2018 ; Colman, 2020 ). Although the whole tissue exhibits APD alternans of in-phase changes when SCA happens, it is a pure electrical mechanism that relies on the non-uniform arrival time of paced excitations, increasing spatial heterogeneity at the same time point ( Qu et al, 2000 ; Huang et al, 2020 ).…”

“…By its nature, SDA has the potential to produce larger spatial repolarization dispersion than SCA, thus promoting unidirectional conduction block and leading to reentry. Experimentally, pact-clamp and optical mapping methods can be used to investigate cardiac alternans in AP and in the intracellular Ca 2+ transient (CaT), as well as the association between the two at the cellular and tissue levels in vitro ( Chou et al, 2017 ; Munoz et al, 2018 ). A schematic diagram of AP and CaT alternans at the cellular and tissue level measured by patch-clamp and optical mapping technology is shown in Figure 1 (detailed experimental methods are shown in the Supplementary Material 1 ).…”

A space-fractional bidomain framework for cardiac electrophysiology: 1D alternans dynamics

“…In such a scenario, mathematical modelling provides a fundamental tool for the investigation and the advanced mechanistic explanation of strongly coupled nonlinear phenomena due to the intrinsic spatio-temporal coupling in cardiac tissue (e.g., [10,11,12]). The Bidomain and Monodomain theoretical frameworks, in particular, have been widely used to assess traveling wave features, recovering several experimental pieces of evidence but still lacking a precise understanding of the critical conditions leading to recurrent cardiac alternans pat-terns [13,14,15,16]. Recently, these models have been further generalised to assess data assimilation and uncertainty quantification procedures that represent a key tool to reconstruct and predict excitation patterns in cardiac tissue with high fidelity [17,18,19,20,21,22].…”