Mechanisms Underlying Interactions Between Low-Frequency Oscillations and Beat-to-Beat Variability of Celullar Ventricular Repolarization in Response to Sympathetic Stimulation: Implications for Arrhythmogenesis

Abstract

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.

Time Course of Low-Frequency Oscillatory Behavior in Human Ventricular Repolarization Following Enhanced Sympathetic Activity and Relation to Arrhythmogenesis

“…Those enhanced magnitudes may facilitate the occurrence of arrhythmic events that can act as triggers for arrhythmias and at the same time they may contribute to a more vulnerable substrate by increasing spatial repolarization inhomogeneities between regions being at different oscillating phases. This increased arrhythmia susceptibility associated with elevated LF oscillations of repolarization has been postulated by in silico studies (Pueyo et al, 2016;Sampedro-Puente et al, 2019) and confirmed by in vivo research on a CAVB dog model (Sprenkeler et al, 2019) as well as clinical studies in postinfarction patients. (Rizas et al, 2017).…”

“…A modified version of the Xie et al (2013) β-adrenergic signaling model was used as a basis to describe phosphorylation levels of cellular protein kinase A (PKA) substrates, as described in Pueyo et al (2016) and Sampedro-Puente et al (2019). The Xie et al (2013) model represents an evolution from the Soltis and Saucerman (2010) signaling model in which I K s phosphorylation and dephosphorylation rate constants were updated to better match experimental observations reported in Liu et al (2012).…”

“…Under conditions associated with high sympathetic tone, as in failing or aged ventricles, sympathetic surge would thus be expected to induce LF oscillations of repolarization with shorter latency. Consequently, due to the less stringent requirements on the time period of sustained sympathetic activation for LF oscillatory behavior to ensue in failing or aged ventricles, this is anticipated to facilitate the occurrence of such oscillations, with the corresponding potentially adverse consequences (Rizas et al, 2014(Rizas et al, , 2017Pueyo et al, 2016;Sampedro-Puente et al, 2019).…”

“…In brief, differential phosphorylation kinetics of calcium (I Ca ) and potassium (I K ) currents upon phasic β-AS as well as changes in calcium cycling and the action of stretch-activated channels (SACs) in response to phasic mechanical stretch have been shown to generate LF oscillations in cellular action potential (AP) duration (APD) (Pueyo et al, 2016). Subsequent studies have additionally investigated inter-individual differences in LF oscillations of ventricular APD, concluding that calcium and potassium currents, I Ca and I K (specifically, the rapid delayed rectifier I Kr and inward rectifier I K1 ), are major ionic modulators of such inter-individudal differences (Sampedro-Puente et al, 2019). Importantly, these identified ionic factors are key for the development of arrhythmic events following enhancement of APD oscillations' magnitude.…”

“…This requisite on a relatively long exposure to enhanced sympathetic activity for repolarization oscillations to develop may explain why experimentally measured APD oscillations appear to come and go and do not remain as sustained oscillations for long recording periods (Hanson et al, 2014). Pueyo et al (2016) and Sampedro-Puente et al (2019) have shown that, upon a sympathetic rise, the cellular ventricular APD shows a global trend of shortening, or brief prolongation followed by more prominent shortening, which masks concurrent LF oscillations overlapping with the global APD trend. The individual and combined roles of β-AS and mechanical stretch in determining the time lapse for LF oscillations to become visibly manifested are yet to be explored.…”