![]() ![]() 8 Based on recent clinical evidence such as the EAST-AFNET 4 trial, treatment strategies for patients with AF are increasingly focused on rhythm control therapy. 7 Even in patients with permanent AF with narrow QRS complex who were hospitalized for HF within the last year, ablation of the atrioventricular junction together with biventricular pacing significantly reduced mortality. 6 Also, other previous trials in patients with AF suggested beneficial effects of rhythm control therapy on cardiac function and other functional outcomes. 5 Early rhythm control improved cardiovascular outcomes in patients with AF lasting ≤1 year as recently demonstrated in the EAST-AFNET 4 trial. ![]() 1– 4 The CASTLE-AF trial demonstrated that rhythm control via catheter ablation may reduce mortality, HF hospitalization, and may improve left ventricular (LV) function in patients with HF with reduced ejection fraction and concomitant AF. ![]() The harmful interaction between AF and LV function may spur scientists and clinicians to understand AF as a disease of the entire heart.Ītrial fibrillation (AF) and heart failure (HF) often coexist in patients and are associated with worsened cardiovascular outcomes. Besides that, our findings may provide a mechanistic rationale for the outcomes of recent clinical trials comparing rhythm and ventricular rate control. Thus, we provide an explanation for the clinically frequently observed deleterious interaction of AF and LV function. We could demonstrate that AF by itself in the absence of tachycardia causes impaired excitation-contraction coupling associated with increased levels of reactive oxygen species and CaMKII-dependent depression of systolic Ca 2+ release. This translational investigation included different patient cohorts and prospective validations using isolated adult human cardiomyocytes and human iPSC-cardiomyocytes. Our study investigated the effects of AF on the human ventricle to provide pathophysiological understanding of the detrimental interaction between AF and LV function. However, the effects of AF on LV function remain unclear. Based on recent clinical trials, treatment strategies for patients with AF are increasingly focused on rhythm control compared with rate control therapy. Arrhythmias are known to eventually cause systolic LV dysfunction. We revealed that reactive oxygen species-dependent activation of Ca 2+/calmodulin-dependent protein kinase IIδc contributes to adverse remodelling of the AF LV.ĪF and LV dysfunction very frequently coexist. CaMKII inhibition and ROS scavenging ameliorated impaired systolic Ca 2+ handling after AF-simulation. CaMKII (Ca 2+/calmodulin-dependent protein kinase IIδc) was found to be more oxidized at Met281/282 in the LV of patients with AF leading to an increased CaMKII activity and consequent increased RyR2 phosphorylation. Mechanistically, reactive oxygen species were higher in the LV of patients with AF. ![]() We detected an increased late Na + current as a potential trigger for the detrimentally altered Ca 2+/Na +-interplay. Moreover, cytosolic Na + concentration was elevated and action potential duration was prolonged after AF-simulation. Seven days of AF-simulation caused reduced systolic Ca 2+ transient amplitude and sarcoplasmic reticulum Ca 2+ load likely because of an increased diastolic sarcoplasmic reticulum Ca 2+ leak. For a standardized investigation of AF-simulation, human iPSC-cardiomyocytes were tested. After 24 hours of AF-simulation, human LV cardiomyocytes from nonfailing donors showed an impaired Ca 2+ transient amplitude. Moreover, normofrequent AF was simulated in vitro using arrhythmic or rhythmic pacing (both at 60 bpm). These results were confirmed in LV cardiomyocytes from nonfailing donors with sinus rhythm or AF. In functional studies, systolic Ca 2+ transient amplitude of LV cardiomyocytes was reduced in patients with AF, while diastolic Ca 2+ levels and Ca 2+ transient kinetics were not statistically different. LV myocardium from patients with sinus rhythm and patients with AF showed no differences in fibrosis. Ventricular myocardium from patients with aortic stenosis and preserved LV function with sinus rhythm or rate-controlled AF was studied. Maier: Nazha Hamdani: Katrin Streckfuss-Bömeke: and Results: Fischer: Simon Sedej: Daniel Scherr: Christof Schmid: Christoph Brochhausen: Gerd Hasenfuß: Lars S. Molina: Nataliya Dybkova: Daniele Camboni: Thomas H. Steffen Pabel: Maria Knierim: Thea Stehle: Felix Alebrand: Michael Paulus: Marcel Sieme: Melissa Herwig: Friedrich Barsch: Thomas Körtl: Arnold Pöppl: Brisca Wenner: Senka Ljubojevic-Holzer: Cristina E. ![]()
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