Effects of Atrial Fibrillation on the Human Ventricle
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Effects of Atrial Fibrillation on the Human Ventricle. / Pabel, Steffen; Knierim, Maria; Stehle, Thea; Felix, Alebrand; Paulus, Michael; Sieme, Marcel; Herwig, Melissa; Barsch, Friedrich; Körtl, Thomas; Pöppl, Arnold; Wenner, Brisca; Ljubojevic-Holzer, Senka; Molina, Cristina; Dybkova, Nataliya; Camboni, Daniele; Fischer, Thomas H; Sedej, Simon; Scherr, Daniel; Schmid, Christof; Brochlausen, Christoph; Hasenfuß, Gerd; Maier, Lars S; Hamdani, Nazha; Streckfuss-Bömeke, Katrin; Sossalla, Samuel.
In: CIRC RES, Vol. 130, No. 7, 04.2022, p. 994-1010.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Effects of Atrial Fibrillation on the Human Ventricle
AU - Pabel, Steffen
AU - Knierim, Maria
AU - Stehle, Thea
AU - Felix, Alebrand
AU - Paulus, Michael
AU - Sieme, Marcel
AU - Herwig, Melissa
AU - Barsch, Friedrich
AU - Körtl, Thomas
AU - Pöppl, Arnold
AU - Wenner, Brisca
AU - Ljubojevic-Holzer, Senka
AU - Molina, Cristina
AU - Dybkova, Nataliya
AU - Camboni, Daniele
AU - Fischer, Thomas H
AU - Sedej, Simon
AU - Scherr, Daniel
AU - Schmid, Christof
AU - Brochlausen, Christoph
AU - Hasenfuß, Gerd
AU - Maier, Lars S
AU - Hamdani, Nazha
AU - Streckfuss-Bömeke, Katrin
AU - Sossalla, Samuel
PY - 2022/4
Y1 - 2022/4
N2 - 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 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.CONCLUSIONS: 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.
AB - 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 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.CONCLUSIONS: 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.
U2 - 10.1161/CIRCRESAHA.121.319718
DO - 10.1161/CIRCRESAHA.121.319718
M3 - SCORING: Journal article
VL - 130
SP - 994
EP - 1010
JO - CIRC RES
JF - CIRC RES
SN - 0009-7330
IS - 7
ER -