Background and Objectives: Enhanced beat-to-beat variability of ventricular repolarization (BVR) has been linked to arrhythmias and sudden cardiac death. Recent experimental studies on human left ventricular epicardial electrograms have shown that BVR closely interacts with low-frequency (LF) oscillations of activation recovery interval during sympathetic provocation. In this work human ventricular computational cell models are developed to reproduce the experimentally observed interactions between BVR and its LF oscillations, to assess underlying mechanisms and to establish a relationship with arrhythmic risk. Materials and Methods: A set of human ventricular action potential (AP) models covering a range of experimental electrophysiological characteristics was constructed. These models incorporated stochasticity in major ionic currents as well as descriptions of β-adrenergic stimulation and mechanical effects to investigate the AP response to enhanced sympathetic activity. Statistical methods based on Automatic Relevance Determination and Canonical Correlation Analysis were developed to unravel individual and common factors contributing to BVR and LF patterning of APD in response to sympathetic provocation. Results: Simulated results reproduced experimental evidences on the interactions between BVR and LF oscillations of AP duration (APD), with replication of the high inter-individual variability observed in both phenomena. I CaL , I Kr and I K1 currents were identified as common ionic modulators of the inter-individual differences in BVR and LF oscillatory behavior and were shown to be crucial in determining susceptibility to arrhythmogenic events. Conclusions: The calibrated family of human ventricular cell models proposed in this study allows reproducing experimentally reported interactions between BVR and LF oscillations of APD. Ionic factors involving I CaL , I Kr and I K1 currents are found to underlie correlated increments in both phenomena in response to sympathetic provocation. A link to arrhythmogenesis is established for concomitantly elevated levels of BVR and its LF oscillations.

Objective: Enhanced spatiotemporal ventricular repolarization variability has been associated with ventricular arrhythmias and sudden cardiac death, but the involved mechanisms remain elusive. In this work a methodology for estimation of parameters and state variables of stochastic human ventricular cell models from input voltage data is proposed for investigation of repolarization variability. Methods: The proposed methodology formulates state-space representations based on developed stochastic cell models and uses the Unscented Kalman Filter (UKF) to perform joint parameter and state estimation. Evaluation over synthetic and experimental data is presented. Results: Results on synthetically generated data show the ability of the methodology to: 1) filter out measurement noise from action potential (AP) traces; 2) identify model parameters and state variables from each of those individual AP traces, thus allowing robust characterization of cell-to-cell variability; and 3) replicate statistical population's distributions of input APbased markers, including dynamic markers quantifying beat-tobeat variability. Application onto experimental data demonstrates the ability of the methodology to match input AP traces while concomitantly inferring the characteristics of underlying stochastic cell models. Conclusion: A novel methodology is presented for estimation of parameters and hidden variables of stochastic cardiac computational models, with the advantage of providing a one-to-one match between each individual AP trace and a corresponding set of model characteristics. Significance: The proposed methodology can greatly help in the characterization of temporal (beat-to-beat) and spatial (cell-to-cell) variability in human ventricular repolarization and in ascertaining the corresponding underlying mechanisms, particularly in scenarios with limited available experimental data.

Background and Objectives: Recent studies in humans and dogs have shown that ventricular repolarization exhibits a low-frequency (LF) oscillatory pattern following enhanced sympathetic activity, which has been related to arrhythmic risk. The appearance of LF oscillations in ventricular repolarization is, however, not immediate, but it may take up to some minutes. This study seeks to characterize the time course of the action potential (AP) duration (APD) oscillatory behavior in response to sympathetic provocations, unveil its underlying mechanisms and establish a potential link to arrhythmogenesis under disease conditions. Materials and Methods: A representative set of human ventricular computational models coupling cellular electrophysiology, calcium dynamics, β-adrenergic signaling, and mechanics was built. Sympathetic provocation was modeled via phasic changes in β-adrenergic stimulation (β-AS) and mechanical stretch at Mayer wave frequencies within the 0.03-0.15 Hz band.Results: Our results show that there are large inter-individual differences in the time lapse for the development of LF oscillations in APD following sympathetic provocation, with some cells requiring just a few seconds and other cells needing more than 3 min. Whereas, the oscillatory response to phasic mechanical stretch is almost immediate, the response to β-AS is much more prolonged, in line with experimentally reported evidences, thus being this component the one driving the slow development of APD oscillations following enhanced sympathetic activity. If β-adrenoceptors are priorly stimulated, the time for APD oscillations to become apparent is remarkably reduced, with the oscillation time lapse being an exponential function of the pre-stimulation level. The major mechanism underlying the delay in APD oscillations appearance is related to the slow I Ks phosphorylation kinetics, with its relevance being modulated by the I Ks conductance of each individual cell. Cells presenting short oscillation time lapses Sampedro-Puente et al. Time Course of Low-Frequency Oscillatory Behavior are commonly associated with large APD oscillation magnitudes, which facilitate the occurrence of pro-arrhythmic events under disease conditions involving calcium overload and reduced repolarization reserve. Conclusions:The time course of LF oscillatory behavior of APD in response to increased sympathetic activity presents high inter-individual variability, which is associated with different expression and PKA phosphorylation kinetics of the I Ks current. Short time lapses in the development of APD oscillations are associated with large oscillatory magnitudes and pro-arrhythmic risk under disease conditions.