Introduction: Atrial fibrillation (AF) and heart failure (HF) often coexist, but their interaction is poorly understood. Clinical data indicate that the arrhythmic component of AF may contribute to left ventricular (LV) dysfunction. This study investigated the effects of AF on the human LV.

Methods and Results: LV myocardium from patients with preserved LV function (EF>50%) with sinus rhythm (SR, n=31) or rate-controlled AF (n=24) obtained during surgery for aortic stenosis was studied. LV myocardium from SR and AF patients showed no differences in fibrosis. In functional studies, systolic Ca²⁺ transient amplitude of isolated human LV cardiomyocytes (CM) was reduced in AF patients, while diastolic Ca²⁺ levels and Ca²⁺ transient kinetics were unaltered. These results were confirmed in LV CM from non-failing donors with AF (n=4) vs. SR (n=8). In addition, normofrequent AF was simulated in vitro using arrhythmic or rhythmic electrical culture pacing (both at 60 bpm). After 24h of AF-simulation, human LV CM from non-failing donors (n=9) showed also an impaired Ca²⁺ transient amplitude. For a standardized chronic AF-simulation, human iPSC-CM (n=22 differentiations/5 individuals) were utilized as a translational model. 7 days of AF-simulation similarly caused reduced systolic Ca²⁺ transient amplitude and sarcoplasmic reticulum Ca²⁺ load, which could be explained by an increased diastolic Ca²⁺ leak. Moreover, cytosolic Na⁺ concentration was elevated, and action potential duration was prolonged after AF-simulation. We detected an increased late Na⁺ current as a potential trigger for the detrimentally altered Ca²⁺/Na⁺-interplay in iPSC-CM after AF-simulation. Mechanistically, oxidative stress markers were higher in the LV of AF patients. Ca²⁺/calmodulin-dependent protein kinase IIδ (CaMKII) was found to be more oxidized at Met281/282 in the LV of AF patients leading to an increased CaMKII activity. Consequently, RyR2 phosphorylation was elevated, which likely underlies the depression of LV Ca²⁺ handling in AF. CaMKII inhibition and ROS scavenging during 7 days of AF-simulation prevented the impaired systolic Ca²⁺ handling in iPSC-CM.

Conclusions: Here we could demonstrate that AF per se impairs human LV excitation-contraction coupling via increases of oxidative stress and CaMKII activity in different patient populations and human models. Thus, this translational study firstly reveals the detrimental effects and mechanisms of AF in the absence of tachycardia on the human LV.