title: Atrial fibrillation complicated by heart failure induces distinct remodeling of calcium cycling proteins.
abstract: Atrial fibrillation (AF) and heart failure (HF) are two of the most common cardiovascular diseases. They often coexist and account for significant morbidity and mortality. Alterations in cellular Ca2+ homeostasis play a critical role in AF initiation and maintenance. This study was designed to specifically elucidate AF-associated remodeling of atrial Ca2+ cycling in the presence of mild HF. AF was induced in domestic pigs by atrial burst pacing. The animals underwent electrophysiologic and echocardiographic examinations. Ca2+ handling proteins were analyzed in right atrial tissue obtained from pigs with AF (day 7; n = 5) and compared to sinus rhythm (SR) controls (n = 5). During AF, animals exhibited reduction of left ventricular ejection fraction (from 73% to 58%) and prolonged atrial refractory periods. AF and HF were associated with suppression of protein kinase A (PKA)RII (-62%) and Ca2+-calmodulin-dependent kinase II (CaMKII) δ by 37%, without changes in CaMKIIδ autophosphorylation. We further detected downregulation of L-type calcium channel (LTCC) subunit α2 (-75%), sarcoplasmic reticulum Ca2+-ATPase (Serca) 2a (-29%), phosphorylated phospholamban (Ser16, -92%; Thr17, -70%), and phospho-ryanodine receptor 2 (RyR2) (Ser2808, -62%). Na+-Ca2+ exchanger (NCX) levels were upregulated (+473%), whereas expression of Ser2814-phosphorylated RyR2 and LTCCα1c subunits was not significantly altered. In conclusion, AF produced distinct arrhythmogenic remodeling of Ca2+ handling in the presence of tachycardia-induced mild HF that is different from AF without structural alterations. The changes may provide a starting point for personalized approaches to AF treatment.
authors.affiliation: Department of Cardiology, Medical University Hospital, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Lugenbiel
authors.affiliation: Department of Cardiology, Medical University Hospital, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Wenz
authors.affiliation: Department of Cardiology, Medical University Hospital, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Govorov
authors.affiliation: Department of Cardiology, Medical University Hospital, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Schweizer
authors.affiliation: Department of Cardiology, Medical University Hospital, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: Department of Cardiology, Medical University Hospital, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
authors.forename: Dierk
authors.initials: D
authors.lastname: Thomas
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000150:complications* / Q000378:metabolism* / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006325:Heart Atria / Q000378:metabolism; D006333:Heart Failure / Q000150:complications*; D008297:Male; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D013552:Swine; D018487:Ventricular Dysfunction, Left
chemical_list: D011506:Proteins; D011494:Protein Kinases; D002118:Calcium