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

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. 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. 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, I and I 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. 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, I and I 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.