Spatially Discordant Repolarization Alternans in the Absence of Conduction Velocity Restitution

Abstract

Spatially discordant alternans (SDA) of action potential duration (APD) has been widely observed in cardiac tissue and is linked to cardiac arrhythmogenesis. Theoretical studies have shown that conduction velocity restitution (CVR) is required for the formation of SDA. However, this theory is not completely supported by experiments, indicating that other mechanisms may exist. In this study, we carried out computer simulations using mathematical models of action potentials to investigate the mechanisms of SDA in cardiac tissue. We show that when CVR is present and engaged, such as fast pacing from one side of the tissue, the spatial pattern of APD in the tissue undergoes either spatially concordant alternans or SDA, independent of initial conditions or tissue heterogeneities. When CVR is not engaged, such as simultaneous pacing of the whole tissue or under normal/slow heart rates, the spatial pattern of APD in the tissue can have multiple solutions, including spatially concordant alternans and different SDA patterns, depending on heterogeneous initial conditions or pre-existing repolarization heterogeneities. In homogeneous tissue, curved nodal lines are not stable, which either evolve into straight lines or disappear. However, in heterogeneous itssue, curved nodal lines can be stable, depending on their initial locations and shapes relative to the structure of the heterogeneity. Therefore, CVR-induced SDA and non-CVR-induced SDA exhibit different dynamical properties, which may be responsible for the different SDA properties observed in experimental studies and arrhythmogenesis in different clinical settings.

Delayed global feedback in the genesis and stability of spatiotemporal excitation patterns in paced biological excitable media

“…Cardiac and neural tissue are typical excitable media. In cardiac tissue, spatially concordant and discordant APD alternans have been widely observed in experiments [ 37 , 62 – 64 ], and mechanisms have been revealed in mathematical modeling and theoretical studies [ 38 , 65 , 66 ]. However, in the real heart, electrical excitations cause mechanical contraction, and the contraction and stretch of the heart cells may result in the opening of the mechano-sensitive ion channels or alteration of intracellular Ca 2+ cycling properties, a phenomenon called mechano-electric feedback [ 34 – 36 ].…”

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

“…It is a pure voltage mechanism that relies on the non-uniform time of arrival of paced excitations. By its nature, SDA has the potential to produce larger spatial repolarization dispersion, and is therefore more likely to promote unidirectional conduction block and leading to reentry ( Wang et al, 2014 , 2018 ; Liu et al, 2015 ; Wei et al, 2015 ; Huang et al, 2020 ). In theory, simulation of the electrical wave propagation in the heart can be used to clarify the mechanisms of reentrant arrhythmia and develop new treatment strategies.…”

“…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.…”

“…Under rapid pacing or pathological conditions, it can be envisaged that tissue’s intrinsic electrophysiological heterogeneities will be further amplified, resulting in an increased spatial dispersion in cardiac excitation/recovery leading to unidirectional or localized conduction block forming substrates for arrhythmias. However, some experimental and simulation studies have shown that pre-existing tissue heterogeneities may not be necessary for the formation of SDA preceding to arrhythmogenesis ( Watanabe et al, 2001 ; Huang et al, 2020 ). It is known that many dynamic properties, such as conduction velocity (CV) restitution ( Wei et al, 2015 ; Wang et al, 2018 ; Huang et al, 2020 ), steep APD restitution curve ( Qu et al, 2000 ; Liu et al, 2015 ; Vandersickel et al, 2016 ), [Ca 2+ ] i cycling instability ( Alvarez-Lacalle et al, 2015 ; Qu et al, 2016 ; Restrepo et al, 2018 ; Song et al, 2018 ), and autonomic nervous system regulation ( Lown and Verrier, 1976 ; Winter et al, 2018 ; Xiong et al, 2018 ) can convert SCA into SDA facilitating arrhythmogenesis.…”

“…One of the reasons for this might be that the original hope that TWA could help in clinical risk stratification is fading away. Importantly, although possible mechanisms of TWA have been investigated in previous studies ( Qu et al, 2000 ; Restrepo et al, 2018 ; Wang et al, 2018 ; Xiong et al, 2018 ; Huang et al, 2020 ), the spontaneous transition from spatially concordant or discordant alternans to arrhythmias is yet to be understood. Given the fact that TWA is associated with arrhythmogenesis, it is of importance to reveal such mechanisms by using both experimental and computational modeling approaches, the results of which may provide critical information that is useful for arrhythmia prevention, diagnosis, and drug intervention.…”