Impaired myofibrillar energetics and oxidative injury during human atrial fibrillation

Background-Atrial. fibrillation (AF) is associated with severe contractile dysfunction and structural and electrophysiological remodeling. Mechanisms responsible for impaired contractility are undefined, and current therapies do not address this dysfunction. We have found that myofibrillar creatine kinase (MM-CK), an important controller of myocyte contractility, is highly sensitive to oxidative injury, and we hypothesized that increased oxidativ e stress and energetic impairment during AF could contribute to contractile dysfunction. Methods and Results-Right atrial appendages were obtained from AF patients undergoing the Maze procedure and from control patients who were in normal sinus rhythm and undergoing cardiac surgery. MM-CK activity was reduced in AF patients compared with controls (25.4 +/-3.4 versus 18.2 +/-3.8 mu mol/m g of myofibrillar protein per minute; control versus AF; P <0.05). No reduc tion in total CK activity or myosin ATPase activity was detected. This sele ctive reduction in MM-CK activity was associated with increased relative ex pression of the P-myosin isoform (25 +/- 6 versus 63 +/-5%beta, CTRL versus AF; P <0.05). Western blotting of AF myofibrillar isolates demonstrated no changes in protein composition but showed increased prevalence of protein oxidation as detected by Western blotting for 3-nitrotyrosine (peroxynitrit e biomarker) and protein carbonyls (hydroxyl radical biomarker; P <0.05). P atterns of these oxidative markers were distinct, which suggests discrete c hemical events and differential protein vulnerabilities in vivo. MM-CK inhi bition was statistically correlated to extent of nitration (P <0.01) but no t to carbonyl presence. Conclusions-The present results provide novel evidence of oxidative damage in human AF that altered myofibrillar energetics may contribute to atrial c ontractile dysfunction and that protein nitration may be an important parti cipant in this condition.