Abstract 308 Atrial fibrillation promotes human left ventricular diastolic dysfunction via nitric oxide pathway

Clin Res Cardiol (2023). https://doi.org/10.1007/s00392-023-02302-4
Atrial fibrillation promotes human left ventricular diastolic dysfunction via nitric oxide pathway
M. Sieme¹, M. Herwig², S. Pabel³, I. Sultana⁴, M. Tangos⁵, K. Streckfuß-Bömeke⁶, I. El-Battrawy⁷, L. van Heerebeek⁸, F. Paneni⁹, W. Schmidt¹⁰, V. S Patel¹¹, A. Mügge¹², Z. Bagi¹³, S. T. Sossalla³, N. Hamdani¹⁴
¹Institut für Forschung und Lehre (IFL), St. Josef Hospital, Ruhr-Universität Bochum, Bochum; ²Molekulare und Experimentelle Kardiologie, Institut für Forschung und Lehre (IFL), St. Josef Hospital, Ruhr-Universität Bochum, Bochum; ³Klinik und Poliklinik für Innere Med. II, Kardiologie, Universitätsklinikum Regensburg, Regensburg; ⁴Molecular and Experimental Cardiology, Interdisziplinäres Institut für Forschung und Lehre, St. Joseph Hospital, Ruhr University Bochum, Bochum; ⁵Abteilung für Zelluläre und Translationale Physiologie, Ruhr-Universität Bochum, Bochum; ⁶Institut für Pharmakologie und Toxikologie, Universitätsklinikum Würzburg, Würzburg; ⁷Medizinische Klinik II, Kardiologie und Angiologie, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil, Bochum; ⁸Cardiology, Heart Center, OLVG Hospital, Amsterdam, NL; ⁹Cardiology, University Hospital Zürich Heart Center, Zürich, CH; ¹⁰Medizinische Klinik 1, St.Josef-Hospital UK RUB, Bochum; ¹¹Physiology and Medicine, Medical College of Georgia, Augusta University, Augusta; ¹²Medizinische Klinik II, Kardiologie, Klinikum der Ruhr-Universität Bochum, Bochum; ¹³Physiology and Medicine, Medical College of Georgia, Augusta University, Augusta, US; ¹⁴Cellular Physiology, Kath. Klinikum Bochum, Bochum;
Introduction: Patients with heart failure with preserved ejection fraction (HFpEF) often develop atrial fibrillation. An impaired diastolic function of the LV leading to elevated filling pressures and subsequent left atrial remodeling can form a potent substrate for atrial fibrillation (AF) induction and perseverance. Thus, LV diastolic dysfunction can precede and even predict AF. On the other hand, disturbed atrial contraction during AF has shown to impair LV filling and hemodynamics^. Whether and how AF may influence diastolic function of LV myocardium remains elusive. This study investigated the potential effects of AF on LV diastolic function in humans. Methods and results: 40 Patients with either rate-controlled AF (n=17) or sinus rhythm (SR, n=23) with preserved LV function (LV ejection fraction >50%) undergoing aortic valve replacement due to aortic stenosis were included and LV myocardium from septal resections was studied. Myofilament stiffness in LV cardiomyocytes was significantly higher in patients with AF compared to SR, which was reversible upon in vitro treatment with proteinkinase G (PKG). We also observed a lower Ca2+-activated max tension of LV cardiomyocytes from AF patients indicating an impaired cardiomyocyte function. These alerations were associated with a reduced phosphorylation of Titin and Troponin I, including a diminished PKG-dependent Titin phosphorylation at Ser4099. Moreover, NO levels were impaired in the LV of AF patients, and this was linked to reduced soluble guanylate cyclase (SGC) activity, lower cyclic guanosine monophosphate (cGMP) levels and impaired PKG activity. In line with the observed reduction in NO bioavailability, isometric tension studies in isolated and pressurized coronary arterioles showed a defective bradykinin-induced endothelium-dependent vasodilatory function in AF patients. For translational purposes, we used in vitro AF-simulation using human ventricular iPSC-cardiomyocytes (hiPSC-CM) from healthy donors undergoing chronic arrhythmic culture pacing (60 bpm, 40% beat-to-beat variability versus 60 bpm in control) for 7 days. After AF-simulation, hiPSC-CM showed reduced NO levels compared to control, which was accompanied by reduced sGC activity and cGMP levels and impaired PKG activity in ventricular hiPSC-CM. These was associated with increased oxidative stress levels, as assessed by 3-nitrotyrosine upon AF in patients and hiPSC-CM and with increased NADPH oxidase 2 (NOX2) and 4 (NOX4) expression in the LV of AF patients. Our work provides mechanistic evidence on how AF per se may be linked to diastolic dysfunction in humans. While diastolic dysfunction strongly increases AF susceptibility, we hypothesize that the interaction between AF and LV diastolic dysfunction is unidirectional and detrimental, thus leading to impaired diastolic performance and increased risk of HFpEF.
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