Abstract:

Life-threatening cardiac arrhythmias require immediate defibrillation. For state-of-the-art shock treatments, a high field strength is required to achieve a sufficient success rate for terminating the complex spiral wave (rotor) dynamics underlying cardiac fibrillation. However, such high energy shocks have many adverse side effects due to the large electric currents applied. In this study, we show, using 2D simulations based on the Fenton-Karma model, that also pulses of relatively low energy may terminate the chaotic activity if applied at the right moment in time. In our simplified model for defibrillation, complex spiral waves are terminated by local perturbations corresponding to conductance heterogeneities acting as virtual electrodes in the presence of an external electric field. We demonstrate that time series of the success rate for low energy shocks exhibit pronounced peaks which correspond to short intervals in time during which perturbations aiming at terminating the chaotic fibrillation state are (much) more successful. Thus, the low energy shock regime, although yielding very low temporal average success rates, exhibits moments in time for which success rates are significantly higher than the average value shown in dose-response curves. This feature might be exploited in future defibrillation protocols for achieving high termination success rates with low or medium pulse energies.

Abstract:

UNLABELLED: Cases of vaccine breakthrough, especially in variants of concern (VOCs) infections, are emerging in coronavirus disease (COVID-19). Due to mutations of structural proteins (SPs) (e.g., Spike proteins), increased transmissibility and risk of escaping from vaccine-induced immunity have been reported amongst the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Remdesivir was the first to be granted emergency use authorization but showed little impact on survival in patients with severe COVID-19. Remdesivir is a prodrug of the nucleoside analogue GS-441524 which is converted into the active nucleotide triphosphate to disrupt viral genome of the conserved non-structural proteins (NSPs) and thus block viral replication. GS-441524 exerts a number of pharmacological advantages over Remdesivir: (1) it needs fewer conversions for bioactivation to nucleotide triphosphate; (2) it requires only nucleoside kinase, while Remdesivir requires several hepato-renal enzymes, for bioactivation; (3) it is a smaller molecule and has a potency for aerosol and oral administration; (4) it is less toxic allowing higher pulmonary concentrations; (5) it is easier to be synthesized. The current article will focus on the discussion of interactions between GS-441524 and NSPs of VOCs to suggest potential application of GS-441524 in breakthrough SARS-CoV-2 infections. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s44231-022-00021-4.

Abstract:

Conduction velocity in cardiac tissue is a crucial electrophysiological parameter for arrhythmia vulnerability. Pathologically reduced conduction velocity facilitates arrhythmogenesis because such conduction velocities decrease the wavelength with which re-entry may occur. Computational studies on CVand how it changes regionally in models at spatial scales multiple times larger than actual cardiac cells exist. However, microscopic conduction within cells and between them have been studied less in simulations. In this work, we study the relation of microscopic conduction patterns and clinically observable macroscopic conduction using an extracellular- membrane-intracellular model which represents cardiac tissue with these subdomains at subcellular resolution. By considering cell arrangement and non-uniform gap junction distribution, it yields anisotropic excitation propagation. This novel kind of model can for example be used to understand how discontinuous conduction on the micro- scopic level affects fractionation of electrograms in healthy and fibrotic tissue. Along the membrane of a cell, we observed a continuously propagating activation wavefront. When transitioning from one cell to the neighbouring one, jumps in local activation times occurred, which led to lower global conduction velocities than locally within each cell.