Expression of Mitochondrial, Contractile, and Calcium Regulatory Proteins is Altered in Patients with Atrial Fibrillation

Introduction: Atrial fibrillation (AF) increases energy demand for contractile and electrical activity. Changes in left atrial (LA) protein expression of AF patients are poorly characterized. Hypothesis: Mitochondrial protein expression in patients with AF is altered in an attempt to meet increased energy demand. Methods: LA appendage tissue was obtained from 198 patients undergoing Maze surgery. At the time of surgery, 80 were in sinus rhythm (SR) (50 paroxysmal AF, 30 persistent AF) and 118 in AF (65 persistent AF, 53 permanent AF). Protein content was assessed by mass spectrometry and 2539 proteins were identified. Results: In AF compared to SR, 257 proteins were differentially expressed (q<0.05); 44 of 62 mitochondrial proteins detected (MitoCarta 3.0) were increased. KEGG pathway analysis revealed Oxidative Phosphorylation was increased (p=1.01E-3) in AF, including 17 subunits of the electron transport chain (A). The Hypertrophic Cardiomyopathy pathway was decreased (p=1.01E-03). Expression of ryanodine receptor, and troponin and tropomyosin subunits decreased, but tropomyosin 4 and myosin heavy chain 9 and 10 increased (B), providing evidence of changes in myofibrillar and calcium regulatory proteins in AF. Among 39 putative AF risk genes detectable at the protein level, 8 were altered in AF (C). The Tricarboxylic Acid Cycle KEGG pathway was decreased (p=2.55E-3) in patients with permanent compared to persistent AF, with no significant changes in other cellular pathways or protein expression of putative AF risk genes. Conclusions: In one of the largest proteomic datasets in human LA to date, we find that expression of proteins in metabolic, myofibrillar, and calcium regulation pathways is altered in patients with AF. Additional metabolic changes were detected with progression to permanent AF. These data identify proteins that are altered in patients with AF providing insight into cellular pathways that may be targeted for AF prevention and therapy.