Effects of Atrial Fibrillation on the Human Ventricle

Atrial fibrillation (AF) and heart failure 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 investigates the effects and molecular mechanisms of AF on the human LV.

Ventricular myocardium from patients with aortic stenosis and preserved LV function with sinus rhythm or rate-controlled AF was studied. LV myocardium from patients with sinus rhythm and patients with AF showed no differences in fibrosis. In functional studies, systolic Ca²⁺ transient amplitude of LV cardiomyocytes was reduced in patients with AF, while diastolic Ca²⁺ levels and Ca²⁺ transient kinetics were not statistically different. These results were confirmed in LV cardiomyocytes from nonfailing donors with sinus rhythm or AF. Moreover, normofrequent AF was simulated in vitro using arrhythmic or rhythmic pacing (both at 60 bpm). After 24 hours of AF-simulation, human LV cardiomyocytes from nonfailing donors showed an impaired Ca²⁺ transient amplitude. For a standardized investigation of AF-simulation, human iPSC-cardiomyocytes were tested. Seven days of AF-simulation caused reduced systolic Ca²⁺ transient amplitude and sarcoplasmic reticulum Ca²⁺ load likely because of an increased diastolic sarcoplasmic reticulum 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. Mechanistically, reactive oxygen species were higher in the LV of patients with AF. CaMKII (Ca²⁺/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. CaMKII inhibition and ROS scavenging ameliorated impaired systolic Ca²⁺ handling after AF-simulation.

AF causes distinct functional and molecular remodeling of the human LV. This translational study provides the first mechanistic characterization and the potential negative impact of AF in the absence of tachycardia on the human ventricle.