Atrial fibrillation begets atrial fibrillation - serum-driven amplification of atrial electrical instability
- 1Deutsches Herzzentrum der Charité, Charité Universitätsmedizin Berlin
Abstract
RationaleAtrial fibrillation (AF) is sustained by electrical triggers and atrial substrate, but whether AF itself generates circulating factors that acutely reinforce arrhythmogenesis is unknown.
ObjectiveTo determine whether rhythm-dependent serum bioactivity directly destabilizes atrial electrophysiology and to identify associated cellular mechanisms and circulating mediators.
Methods and ResultsCardiac samples were obtained from patients with persistent atrial fibrillation (AF) during AF and after restoration of sinus rhythm (SR) using electrical cardioversion. In isolated Langendorff-perfused mouse hearts, AF serum increased the duration, frequency, and cumulative burden of spontaneous atrial depolarizations compared with paired control perfusate. In human induced pluripotent stem cell derived atrial cardiomyocytes, AF patient serum decreased Ca{superscript 2}-transient amplitudes without significant effect on kinetics or Ca{superscript 2} spark activity. Moreover, AF serum reduced peak sodium current without materially altering voltage-dependent gating or paced action-potential properties. Data-independent acquisition proteomics identified rhythm-associated changes in extracellular-matrix, proteolytic, inflammatory, and signaling proteins, including MMP9, Ccathepsin G, and 14-3-3 family members. Targeted pathway perturbation differentially modified serum-induced Ca{superscript 2} phenotypes, indicating context-dependent, multifactorial bioactivity. Serum-induced Ca{superscript 2} responses were not associated with indices of atrial disease severity, including low-voltage substrate burden and left atrial pressure.
ConclusionsPersistent AF is accompanied by rhythm-dependent circulating bioactivity that acutely promotes atrial electrical instability and Ca{superscript 2}-dependent trigger formation. These findings extend the concept that "AF begets AF" beyond tissue-intrinsic remodeling and identify a potentially reversible serum-mediated feed-forward mechanism linking rhythm status and circulating proteomic signals in an atrial substrate severity independent fashion.
Related
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BibTeX
@misc{bogner2026atrial,
title = {{Atrial fibrillation begets atrial fibrillation - serum-driven amplification of atrial electrical instability}},
author = {M. Bögner and G. Ramesh and P. Fahjen and J. Hüttemeister and M. Kirk and E. Heil and M. Bock and K. Zhang and G. Boehm and L. Eichelmann and J. H. Gerds-Li and I. Hilgendorf and V. Falk and P. Mertins and G. Hindricks and F. Hohendanner},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.09.26365177},
url = {https://www.medrxiv.org/content/10.64898/2026.10.09.26365177v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Atrial fibrillation begets atrial fibrillation - serum-driven amplification of atrial electrical instability
AU - M. Bögner
AU - G. Ramesh
AU - P. Fahjen
AU - J. Hüttemeister
AU - M. Kirk
AU - E. Heil
AU - M. Bock
AU - K. Zhang
AU - G. Boehm
AU - L. Eichelmann
AU - J. H. Gerds-Li
AU - I. Hilgendorf
AU - V. Falk
AU - P. Mertins
AU - G. Hindricks
AU - F. Hohendanner
PY - 2026
DA - 2026/10/09
PB - medRxiv
DO - 10.64898/2026.10.09.26365177
UR - https://www.medrxiv.org/content/10.64898/2026.10.09.26365177v1
AB - RationaleAtrial fibrillation (AF) is sustained by electrical triggers and atrial substrate, but whether AF itself generates circulating factors that acutely reinforce arrhythmogenesis is unknown. ObjectiveTo determine whether rhythm-dependent serum bioactivity directly destabilizes atrial electrophysiology and to identify associated cellular mechanisms and circulating mediators. Methods and ResultsCardiac samples were obtained from patients with persistent atrial fibrillation (AF) during AF and after restoration of sinus rhythm (SR) using electrical cardioversion. In isolated Langendorff-perfused mouse hearts, AF serum increased the duration, frequency, and cumulative burden of spontaneous atrial depolarizations compared with paired control perfusate. In human induced pluripotent stem cell derived atrial cardiomyocytes, AF patient serum decreased Ca{superscript 2}-transient amplitudes without significant effect on kinetics or Ca{superscript 2} spark activity. Moreover, AF serum reduced peak sodium current without materially altering voltage-dependent gating or paced action-potential properties. Data-independent acquisition proteomics identified rhythm-associated changes in extracellular-matrix, proteolytic, inflammatory, and signaling proteins, including MMP9, Ccathepsin G, and 14-3-3 family members. Targeted pathway perturbation differentially modified serum-induced Ca{superscript 2} phenotypes, indicating context-dependent, multifactorial bioactivity. Serum-induced Ca{superscript 2} responses were not associated with indices of atrial disease severity, including low-voltage substrate burden and left atrial pressure. ConclusionsPersistent AF is accompanied by rhythm-dependent circulating bioactivity that acutely promotes atrial electrical instability and Ca{superscript 2}-dependent trigger formation. These findings extend the concept that "AF begets AF" beyond tissue-intrinsic remodeling and identify a potentially reversible serum-mediated feed-forward mechanism linking rhythm status and circulating proteomic signals in an atrial substrate severity independent fashion.
ER -