The Interrelations among Stochastic Pacing, Stability, and Memory in the Heart

Abstract

Low pacing variability in the heart has been clinically reported as a risk factor for lethal cardiac arrhythmias and arrhythmic death. In ia previous simulation study, we demonstrated that stochastic pacing sustains an antiarrhythmic effect by moderating the slope of the action potential duration (APD) restitution curve, by reducing the propensity of APD alternans, converting discordant to concordant alternans, and ultimately preventing wavebreaks. However, the dynamic mechanisms relating pacing stochasticity to tissue stability are not yet known. In this work, we develop a mathematical framework to describe the APD signal using an autoregressive stochastic model, and we establish the interrelations between stochastic pacing, cardiac memory, and cardiac stability, as manifested by the degree of APD alternans. Employing stability analysis tools, we show that increased stochasticity in the ventricular tissue activation sequence works to lower the maximal absolute eigenvalues of the stochastic model, thereby contributing to increased stability. We also show that the memory coefficients of the autoregressive model are modulated by pacing stochasticity in a nonlinear, biphasic way, so that for exceedingly high levels of pacing stochasticity, the antiarrhythmic effect is hampered by increasing APD variance. This work may contribute to establishment of an optimal antiarrhythmic pacing protocol in a future study.

Validation of the Area1 of Approximate Entropy (a1ApEn) in Empirical Data of Heart Rate

“…Therefore, the scaling profile of the complexity estimator a1ApEn clearly indicates that the cardiac control operates as a pseudo-random system, irrespectively of the metabolic demand (in the range here studied). These results confirm a preliminary analysis of our group [19] and are aligned with recent results and interpretations about cardiac control [24][25][26][27].…”

Short-term action potential memory and electrical restitution: A cellular computational study on the stability of cardiac repolarization under dynamic pacing

“…the ability to restore a given average AP waveform after a transient perturbation of pacing rate), and short-term memory (i.e. the dependence of an APD on preceding activation properties, such as APDs, DIs, or even ion concentrations) [ 15 , 16 , 17 ]. A widely adopted but still controversial marker of repolarization stability is the ER slope [ 18 , 19 ], frequently used for example to test the antiarrhythmic potential of pharmacological interventions [ 20 ].…”

Impaired Sarcoplasmic Reticulum Calcium Uptake and Release Promote Electromechanically and Spatially Discordant Alternans: A Computational Study

“…19 Coupled maps have been expanded to account for the influence of memory on APD. [20][21][22][23][24] However, it is dif ficult to make mechanistic predictions using these models, since memory effects are typically collectively encompassed by one or two variables and a few parameters that govern the time scale and relative influence of memory. Although it is clear that alternans can arise at the cellular level via instabilities in both electrical and Ca signaling, experimental evidence in recent years has suggested that Cadriven instabilities may be the primary mechanism underlying alternans formation, 4,10,14 demonstrating the need to specifically account for intracellu lar Ca signaling, in particular sarcoplasmic reticulum (SR) Ca handling, in computational models.…”