https://doi.org/10.1007/s00392-025-02625-4
1Universitätsklinikum Regensburg Klinik und Poliklinik für Innere Med. II, Kardiologie Regensburg, Deutschland; 2Universitätsmedizin Göttingen Herzzentrum, Klinik für Kardiologie und Pneumologie Göttingen, Deutschland; 3Universitätsklinikum Gießen und Marburg GmbH Medizinische Klinik I - Kardiologie und Angiologie Gießen, Deutschland; 4Universitätsklinikum Leipzig Klinik und Poliklinik für Kardiologie Leipzig, Deutschland; 5Universitätsklinikum Regensburg Herz-, Thorax- und herznahe Gefäßchirurgie Regensburg, Deutschland; 6Universitätsmedizin Göttingen Thorax-, Herz- und Gefäßchirurgie Göttingen, Deutschland
Background: In patients with atrial fibrillation (AF) ventricular arrhythmias are a leading cause of death. This study aims to identify potential mechanisms by which atrial fibrillation (AF) promotes ventricular arrhythmias.
Methods and results: The ventricular phenotype in AF patients was characterized using human ventricular myocardium samples from individuals with normal ejection fraction and either sinus rhythm (SR) or AF (EF > 50%, LV myocardium from aortic valve replacement surgery, comparable clinical characteristics). Whole-cell current clamp experiments were conducted in isolated human ventricular cardiomyocytes. In cells from AF patients, delayed afterdepolarizations (DADs) were significantly more frequent (8.87±1.59 DADs/min, n=44 cardiomyocytes/ 11 patients) compared to SR patients (4.06±0.76 DADs/min, n=59/15).
Confocal microscopy (Fluo-4 AM) revealed that a significantly higher proportion of ventricular cardiomyocytes from AF patients exhibited diastolic Ca²⁺ waves (20%, n=60/5) compared to SR patients (7.2%, n=134/10). To further investigate these findings, we conducted in-vitro AF simulation in murine ventricular cardiomyocytes by electric pacing at 60 bpm with a beat-to-beat variability of 40%. AF simulation led to a higher occurrence rate of DADs (9.10±1.25 DADs/min, n=51 cardiomyocytes/ 22 mice) compared to SR simulation (6.19±1.06 DADs/min, n=46/22). Confocal measurements identified increased occurrence of diastolic Ca2+ waves and a higher diastolic Ca²⁺ leak in form of elevated Ca²⁺ spark frequency after AF simulation compared to SR simulation (n=95-112/11-14 mice each). Using Western blot analysis of murine ventricular cardiomyocytes, we uncovered that AF-simulation was associated with increased oxidation of CaMKII at the regulatory Met281/282 oxidation site, which is known to increase CaMKII activity (n=10 mice each). To test the involvement of oxidative CaMKII activation in the proarrhythmic effects of AF on the ventricle we genetically ablated the CaMKII oxidation site (Met281/282) in MMVV knock-in mice. In ventricular cardiomyocytes from MMVV mice after AF simulation, we observed no significant difference in the number of DADs between SR simulation (n=27/8) and AF simulation (n=22/6). In MMVV mice, AF simulation did not change diastolic Ca2+ wave frequency or diastolic Ca2+ spark frequency (n=102-119/13 each).
Conclusion: Our study reveals that AF is associated with increased ventricular arrhythmic triggers in patients. We could demonstrate that AF promotes ventricular arrhythmogenesis by altered Ca2+ handling and an oxidative activation of CaMKII. These findings offer new mechanistic insights and potential therapeutic strategies for addressing the link between AF and ventricular arrhythmias.