Atrial fibrillation complicated by heart failure induces distinct remodeling of calcium cycling proteins

• Published in: PloS one 2015-03, Vol.10 (3), p.e0116395-e0116395
• Main Authors: Lugenbiel, Patrick, Wenz, Fabian, Govorov, Katharina, Schweizer, Patrick A, Katus, Hugo A, Thomas, Dierk
• Format: Article
• Language: English
• Subjects: Alterations; Analysis; Animals; ATPases; Atrial fibrillation; Atrial Fibrillation - complications; Atrial Fibrillation - metabolism; Atrial Fibrillation - physiopathology; Ca2+-transporting ATPase; Ca2+/calmodulin-dependent protein kinase II; Calcium; Calcium (reticular); Calcium - metabolism; Calcium channels; Calcium channels (L-type); Calcium homeostasis; Calcium ions; Calcium-binding protein; Calmodulin; Cardiac arrhythmia; Cardiology; Cardiovascular diseases; Cycles; Dogs; Female; Fibrillation; Gene Expression Regulation, Enzymologic; Heart; Heart Atria - metabolism; Heart diseases; Heart failure; Heart Failure - complications; Homeostasis; Kinases; Laboratory animals; Male; Morbidity; Na+/Ca2+ exchanger; Na+/Ca2+-exchanging ATPase; Phospholamban; Phosphorylation; Pigs; Protein kinase A; Protein Kinases - metabolism; Proteins; Proteins - metabolism; Remodeling; Ryanodine receptors; Sarcoplasmic reticulum; Sinus; Sinuses; Swine; Tachycardia; Ventricle; Ventricular Dysfunction, Left
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0116395

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.