Effects of Atrial Fibrillation on the Human Ventricle

Abstract

Rationale: 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. Objective: This study investigates the effects and molecular mechanisms of AF on the human LV. Methods and Results: Ventricular myocardium from patients with aortic stenosis and preserved LV function with sinus rhythm or rate-controlled AF was studied. LV myocardium from sinus rhythm and patients with AF showed no differences in fibrosis. 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. 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 Ca 2+ transient amplitude. For a standardized investigation of AF-simulation, human iPSC-cardiomyocytes were tested. 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. 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 Ca 2+ /Na + -interplay. Mechanistically, reactive oxygen species were higher in the LV of patients with AF. 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. CaMKII inhibition and ROS scavenging prevented impaired systolic Ca 2+ handling after AF simulation. Conclusions: AF causes distinct functional remodeling of the human LV via detrimental effects on cardiomyocyte excitation-contraction coupling. This translational study provides the first mechanistic characterization and the potential negative impact of AF in the absence of tachycardia on the human ventricle.

Heart Failure and Atrial Fibrillation—Chicken or Egg?

“…This study by Pabel et al 13 is a welcome addition to our limited understanding of the mechanisms linking AF and HF. Previous efforts have focused mostly on tachycardia-induced ventricular remodeling (tachycardia-mediated cardiomyopathy) in the context of AF; however, this current study focuses on the effect of irregular stimulation, per se, without tachycardia on the LV.…”

“…Excessive and persistent Ca 2+ /Calmodulin-independent CaMKII activation is a highly validated pathological mechanism involved in AF 10,11 and HF. 12…”

“…The study by Pabel et al further validates a central role for oxidized CaMKII/CaMKII in AF, 10,11 and HF. 12…”

“…In this issue of Circulation Research , Pabel et al 13 investigated the effects of persistent or permanent AF in left ventricular (LV) biopsies obtained during surgical aortic valve replacement (SAVR) from patients (n=24) with controlled ventricular rate response (mean rates of 79±18 bpm), aortic stenosis, and preserved LV function (EF≥50%). These samples were compared against similar LV biopsies from patients undergoing SAVR for aortic stenosis who were in sinus rhythm (SR, 31 patients).…”

Arrhythmias as Presentation of Genetic Cardiomyopathy

“…This has been attributed to rapid ventricular response, but also to the irregularity of AF, which may cause impairment in cardiomyocyte excitation-contraction coupling. 38…”