20.500.12556/DKUM-89241 Effects of atrial fibrillation on the human ventricle 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. atrial fibrillation calcium-calmodulin-dependent protein kinase type 2 excitation contraction coupling heart failure oxidative stress atrijska fibrilacija od kalcija in kalmodulina odvisna proteinska kinaza tipa 2 vezava vzbujanja in krčenja srčno popuščanje oksidativni stres true false true Lippincott Williams & Wilkins, Highwire Press Angleški jezik Slovenski jezik Znanstveno delo 2024-06-28 09:48:52 2024-06-28 10:17:47 2024-06-29 03:56:40 0000-00-00 00:00:00 2022 0 0 Str. 994-1010 Št. 7 Letn. 130 2022 0000-00-00 Zaloznikova Objavljeno NiDoloceno 2021-06-21 2022-02-14 2022-02-23 616.12 159646723 10.1161/CIRCRESAHA.121.319718 1524-4571 Pabel-2022-Effects_of_Atrial_Fibrillation_on_t.pdf Pabel-2022-Effects_of_Atrial_Fibrillation_on_t.pdf 1 40AD75E67AFF2F8E3F1A927CBECA3238 ed209001685ce6824bcc8504efbeb6493d5a883953155b3f75e04e14fa546d90 9bb38880-3526-11ef-8d5f-00155d000105 https://dk.um.si/Dokument.php?lang=slv&id=180875 https://doi.org/10.1161/CIRCRESAHA.121.319718 0 e0279330-3522-11ef-8d5f-00155d000105 https://dk.um.si/Dokument.php?lang=slv&id=180874 Medicinska fakulteta 0 0 0