Stochastic pacing reveals the propensity to cardiac action potential alternans and uncovers its underlying dynamics

Abstract

Key pointsr Beat-to-beat alternation (alternans) of the cardiac action potential duration is known to precipitate life-threatening arrhythmias and can be driven by the kinetics of voltage-gated membrane currents or by instabilities in intracellular calcium fluxes.r To prevent alternans and associated arrhythmias, suitable markers must be developed to quantify the susceptibility to alternans; previous theoretical studies showed that the eigenvalue of the alternating eigenmode represents an ideal marker of alternans.r Using rabbit ventricular myocytes, we show that this eigenvalue can be estimated in practice by pacing these cells at intervals varying stochastically.r We also show that stochastic pacing permits the estimation of further markers distinguishing between voltage-driven and calcium-driven alternans.r Our study opens the perspective to use stochastic pacing during clinical investigations and in patients with implanted pacing devices to determine the susceptibility to, and the type of alternans, which are both important to guide preventive or therapeutic measures.Abstract Alternans of the cardiac action potential (AP) duration (APD) is a well-known arrhythmogenic mechanism. APD depends on several preceding diastolic intervals (DIs) and APDs, which complicates the prediction of alternans. Previous theoretical studies pinpointed a marker called λ alt that directly quantifies how an alternating perturbation persists over successive APs. When the propensity to alternans increases, λ alt decreases from 0 to -1. Our aim was to quantify λ alt experimentally using stochastic pacing and to examine whether stochastic pacing allows discriminating between voltage-driven and Ca 2+ -driven alternans. APs were recorded in rabbit ventricular myocytes paced at cycle lengths (CLs) decreasing progressively and incorporating stochastic variations. Fitting APD with a function of two previous APDs and CLs permitted us to estimate λ alt along with additional markers characterizing whether the dependence of APD on previous DIs or CLs is strong (typical for voltage-driven alternans) or weak (Ca 2+ -driven alternans). During the recordings, λ alt gradually decreased from around 0 towards -1. Intermittent alternans appeared when λ alt reached -0.8 and was followed by sustained alternans. The additional markers detected that alternans was Ca 2+ driven in control experiments and voltage driven in the presence of ryanodine. This distinction could be made even before alternans was manifest (specificity/sensitivity >80% for -0.4 > λ alt > -0.5). These observations were confirmed in a mathematical model of a rabbit ventricular myocyte. In conclusion, stochastic pacing allows the practical estimation of λ alt to reveal the onset of alternans and distinguishes between voltage-driven and Ca 2+ -driven mechanisms, which is important since these two mechanisms may precipitate arrhythmias in different manners.

Stochastic Pacing Inhibits Spatially Discordant Cardiac Alternans

“…In this work, we investigate a simpler situation where the cycle length is drawn from a Gaussian distribution. Other numerical (58) and experimental (59) studies have observed that in single cardiomyocytes, even small amounts of variance in the pacing rate can contribute to the formation of cardiac alternans, with the resulting interpretation that HRV might be proarrhythmic. Based on the results to follow, we come to a different conclusion: on one-(1-D) and two-dimensional (2-D) domains with single-site pacing in simulations of healthy, homogeneous, and isotropic ventricular tissue, as the variance in the pacing rate increases, the propensity for the tissue to exhibit discordant alternans decreases.…”

George Ralph Mines (1886–1914): the dawn of cardiac nonlinear dynamics

“…The increased fluctuations seen as one approaches a period‐doubling bifurcation have been very recently considered in two situations using interventions that are capable of provoking arrhythmias: fast pacing (Prudat et al . in this issue) and administration of a potassium channel blocker (Quail et al . ).…”

“…In a similar vein, in this issue Trayanova & Chang (2016) describe how one can use MRI mapping, combined with computer simulation, to determine the risk for ventricular tachycardia and fibrillation and to help guide ablations in the clinic, while Jacquemet (2016) discusses modelling of six different targets for ablation in atrial fibrillation. The increased fluctuations seen as one approaches a period-doubling bifurcation have been very recently considered in two situations using interventions that are capable of provoking arrhythmias: fast pacing (Prudat et al 2016 in this issue) and administration of a potassium channel blocker (Quail et al 2015). In a perspective on the former article in this issue, Vandenberg & Hill (2016) suggest that analysis of cardiac alternans might be useful in improving management of patients at risk for sudden cardiac death.…”

Cardiac dynamic assessment through entropy proportions and probability

“…In general, mathematical and physical perspective has led to models that may study physiological mechanisms [4], through the analysis of several variables with mathematical and physiological implications [5]. Symbolic dynamics for the cardiac dynamic variability have been studied [6,7].…”