Oscillatory ACh Release Impact on f-Wave Frequency Modulation: an Experimentally-Based Computational Study

Chiara Celotto1, Carlos Sánchez2, Konstantinos Mountris3, Mostafa Abdollahpur4, Frida Sandberg5, Pablo Laguna6, Esther Pueyo1
1University of Zaragoza, 2Centro Universitario de la Defensa de Zaragoza, 3Aragon Institute of Engineering Research, University of Zaragoza, IIS Aragon, 4Ph.D. Student at Lund University, 5Lund University, 6Zaragoza University


Parasympathetic neurotransmitter acetylcholine (ACh) shortens action potential duration in a dose dependent manner, which facilitates atrial fibrillation (AF) by reducing wavelength for reentry. Dominant f-wave frequency, F_f, exhibits significant variation, 〖∆F〗f, and previous studies suggest that some of this variation relates to respiratory modulation. In this study, we tested the hypothesis that this could be related to [ACh] release pattern. Electrocardiograms were recorded from seven patients during controlled respiration, before and after injection of atropine (ACh inhibitor), from which f-wave frequency modulation was characterized. Experimentally-based electrophysiological simulations in 2D human atrial tissue were performed to assess the effects of [ACh] release pattern on Ff. To mimic AF substrate, electrophysiological remodeling and 20% diffusive fibrosis were simulated. A cross-stimulation protocol was applied onto the tissue to initiate a rotor while cyclically varying [ACh] following a sinusoidal waveform of frequency equal to 0.125 Hz. Different mean levels (0.05, 0.075 µM) and peak-to-peak ranges (0.1, 0.05, 0.025 µM) of [ACh] variation were tested. In all patients, an f-wave frequency modulation could be observed. In 57% of the patients, this modulation was significantly reduced after injection of atropine, supporting our hypothesis of a relationship with ACh release. From the simulations, we confirmed that rotor frequency variations followed the induced [ACh] patterns. The mean frequency of the rotor was dependent on mean [ACh] level, while the magnitude of frequency variation was dependent on [ACh] variation range (see Table). An [ACh] variation of 0.025 µM around a mean value of 0.05 µM was the one providing results closer to those measured from the patients. In conclusion, the pattern of [ACh] release could be an important factor involved in f-wave frequency modulation. Further studies to understand the contribution of other factors and to ascertain whether [ACh] variations could be monitored from f-wave analysis are needed.