Abstract
Purpose: Rotor stability and meandering are key mechanisms determining and sustaining cardiac fibrillation, with important implications for anti-arrhythmic drug development. However, little is yet known on how rotor dynamics are modulated by variability in cellular electrophysiology, particularly on kinetic properties of ion channel recovery.Methods: We propose a novel emulation approach, based on Gaussian process regression augmented with machine learning, for data enrichment, automatic detection, classification, and analysis of re-entrant biomarkers in cardiac tissue. More than 5,000 monodomain simulations of long-lasting arrhythmic episodes with Fenton-Karma ionic dynamics, further enriched by emulation to 80 million electrophysiological scenarios, were conducted to investigate the role of variability in ion channel densities and kinetics in modulating rotor-driven arrhythmic behavior.Results: Our methods predicted the class of excitation behavior with classification accuracy up to 96%, and emulation effectively predicted frequency, stability, and spatial biomarkers of functional re-entry. We demonstrate that the excitation wavelength interpretation of re-entrant behavior hides critical information about rotor persistence and devolution into fibrillation. In particular, whereas action potential duration directly modulates rotor frequency and meandering, critical windows of excitability are identified as the main determinants of breakup. Further novel electrophysiological insights of particular relevance for ventricular arrhythmias arise from our multivariate analysis, including the role of incomplete activation of slow inward currents in mediating tissue rate-dependence and dispersion of repolarization, and the emergence of slow recovery of excitability as a significant promoter of this mechanism of dispersion and increased arrhythmic risk.Conclusions: Our results mechanistically explain pro-arrhythmic effects of class Ic anti-arrhythmics in the ventricles despite their established role in the pharmacological management of atrial fibrillation. This is mediated by their slow recovery of excitability mode of action, promoting incomplete activation of slow inward currents and therefore increased dispersion of repolarization, given the larger influence of these currents in modulating the action potential in the ventricles compared to the atria. These results exemplify the potential of emulation techniques in elucidating novel mechanisms of arrhythmia and further application to cardiac electrophysiology.
Highlights
Self-sustaining patterns of aberrant excitation in the heart, reentries, are the cause of dangerously accelerated heartrates and complete losses of synchronized action (Wit and Cranefield, 1978)
Arrhythmic risk is commonly analyzed in terms of “excitation wavelength” (Smeets et al, 1986; Rensma et al, 1988; Tse and Yan, 2017), the product of conduction velocity (CV) and the effective refractory period (ERP) or action potential duration (APD)
We demonstrate and validate our technique by emulating a suite of spatial biomarkers directly related to arrhythmic risk, and apply it to investigate the generation and persistence of rotor-derived tachycardic and fibrillatory excitation behaviors when all important factors modulating tissue excitability and refractoriness are allowed to simultaneously vary
Summary
Self-sustaining patterns of aberrant excitation in the heart, reentries, are the cause of dangerously accelerated heartrates (tachycardia) and complete losses of synchronized action (fibrillation) (Wit and Cranefield, 1978). Arrhythmic risk is commonly analyzed in terms of “excitation wavelength” (Smeets et al, 1986; Rensma et al, 1988; Tse and Yan, 2017), the product of conduction velocity (CV) and the effective refractory period (ERP) or action potential duration (APD) This determines the minimum length for which reentrant circuits will sustain electrical activity, and increasing wavelength discourages re-entry formation and maintenance (Wiener and Rosenblueth, 1946), and explains the mechanism of action for many anti-arrhythmic drug therapies (Wang et al, 1992). Of particular interest is post-repolarization refractoriness, given confounding evidence that suggests it as both an anti-arrhythmic and pro-arrhythmic mechanism (Kanki et al, 1998; Kirchhof et al, 1998; Muñoz et al, 2007; Coronel et al, 2012; Franz et al, 2014; Cabo, 2015)
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