In Silico Investigation of Inflammation-Mediated Postoperative Atrial Fibrillation

Julian Mierisch1, Moritz Linder1, Axel Loewe2
1Institute of Biomedical Engineering, Karlsruhe Institute of Technology (KIT), 2Karlsruhe Institute of Technology (KIT)


Abstract

Postoperative atrial fibrillation (POAF) affects up to 30% of cardiac surgery patients and peaks two to four days post-operatively, coinciding with the acute peri-operative inflammatory response. Although elevated cytokines are consistently associated with POAF onset, the electrophysiological contributions of individual mediators, and their combined action on overlapping ion-channel targets, remain poorly understood. We integrated experimentally observed ion-channel modulation by IL-1β, IL-6, TNF-α, and TGF-β1 into the Courtemanche-Ramirez-Nattel human atrial cardiomyocyte model. Patch-clamp and dose-response data from the literature were translated into concentration-dependent Hill-type scaling functions for each affected conductance, and a dominant-effect ceiling rule was applied where multiple cytokines target the same channel. Single-cell simulations in openCARP were pre-paced at a basic-cycle-length of 500 ms for 400 beats, and each cytokine concentration was swept from 10% to 100% of its experimental calibration value, individually and in combination. IL-6 emerged as the dominant modifier, prolonging APD90​ by +30% through synergistic IKr inhibition, ICaL upregulation, and SERCA suppression, consistent with the clinical primacy of IL-6 as a POAF predictor. IL-1β shortened APD90 by -20% via ICaL suppression, and TNF-α produced -8% shortening. TGF-β1 displayed qualitatively distinct behaviour: a loss of spike-and-notch morphology, suppressed upstroke, and an abrupt period-2 alternans above 90% of its calibration concentration with beat-to-beat APD90 swings of ≈40%. The combined sweep was non-linear: Ca²⁺ transient amplitude collapsed, diastolic Ca²⁺ rose, and upstroke velocity fell from ≈145 to ≈40 mV/ms at high inflammatory loads. These results identify IL-6 as the primary driver of inflammation-induced APD prolongation and TGF-β1-induced alternans as an atrial-specific pro-arrhythmic mechanism​, providing a mechanistic basis for the POAF substrate.