Clin Res Cardiol (2023). https://doi.org/10.1007/s00392-023-02180-w

Time course and mechanisms of atrial fibrillation-induced left ventricular dysfunction and recovery in human ventricular myocardium

L. Stengel1, T. Walter1, D. Riedl2, T. Körtl2, A. Renner3, J. Gummert3, L. S. Maier2, K. Streckfuß-Bömeke4, S. Pabel2, S. T. Sossalla2

1Klinik für Innere Medizin II, Universisätsklinikum Regensburg, Regensburg; 2Klinik und Poliklinik für Innere Med. II, Kardiologie, Universitätsklinikum Regensburg, Regensburg; 3Klinik für Thorax- und Kardiovaskularchirurgie, Herz- und Diabeteszentrum NRW, Bad Oeynhausen; 4Institut für Pharmakologie und Toxikologie, Universitätsklinikum Würzburg, Würzburg;

Introduction: Atrial fibrillation (AF) often coexists with heart failure (HF). However, interaction remains poorly understood. Clinical studies in patients with AF and HF demonstrated an improved left ventricular (LV) function and mortality after rhythm AF- catheter ablation. However, the underlying myocardial processes after AF termination leading to improved LV function are unclear. Objective: This study investigated effects of AF and its termination on human ventricular myocardium. Methods and Results: Twitching human LV tissue slices from patients with end-stage HF were long-term cultivated and examined in vitro. AF was simulated by application of a tachy-arrhythmic culture pacing at 100 bpm with 30% beat-to-beat variability (vs. 60 bpm/0% in control). Contractility of LV myocardium was assessed. AF simulation caused a progressive decline in systolic force in human LV myocardium (n=9, from 5 hearts) leading to a significantly reduced twitch amplitude after 7 days of AF simulation compared to the control (n=6/5), while diastolic tension did not change.  Rhythm restoration was simulated by switching from AF to sinus rhythm simulation after 7 days and continuing pacing at 60 bpm/0%. Already 5 days after AF termination we observed an improvement of LV function with recovered systolic contraction amplitudes (n=6/4).  To elucidate potential mechanisms in human cardiomyocytes, we utilized human iPSC-cardiomyocytes (iPSC-CM), n=4 differentiations). Epifluorescence microscopy measurements using Fura-2 showed that 7 days of AF-simulation caused a significantly reduced systolic Ca2+ transient amplitude (n=41 cells) compared to control (60 bpm/0%, n=44 cells). Of note, diastolic Ca2+ levels and Ca2+ transient kinetics were not affected. 5 days of sinus rhythm following AF simulation, iPSC-CM showed no difference in Ca2+ transient amplitude anymore (n=41) compared to control (n=28) indicating a recovery of systolic Ca2+ cycling. As an underlying mechanism of systolic Ca2+ transient regulation we identified in confocal microscopy line-scans (Fluo-4) an increased diastolic Ca2+ release after 7 days of AF simulation (n=19) compared to control (n=27), which could be reversed after 5 days following from AF simulation in iPSC-CM (n=15, control n=16 cells). These mechanisms could explain the contractile response to AF in human myocardium. Conclusion: This study demonstrates that AF per se impairs human LV function in HF patients. The involved changes in cardiomyocyte Ca2+ handling are reversible upon AF termination leading to improved LV function already within few days after AF cessation. Identification of these mechanisms may help to potentially treat contractile dysfunction in the high fraction of patients with HF and permanent AF.

https://dgk.org/kongress_programme/jt2023/aV422.html