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(Circulation. 2001;104:174.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Impaired Myofibrillar Energetics and Oxidative Injury During Human Atrial Fibrillation
From the Cardiothoracic Surgery/Kaufman Center for Heart Failure (P.M.M.); Department of Cardiology (D.V.W.), Cleveland Clinic Foundation, Cleveland, Ohio; and the Division of Pharmacology/College of Pharmacy (M.J.M., F.Y., C.A.C., D.V.W., J.A.B.), OSU Heart and Lung Institute (J.A.B.), and College of Dentistry (P.J.R.); Ohio State University, Columbus, Ohio.
Correspondence to John Anthony Bauer, Ohio State University, 500 W 12th Ave, Columbus, OH 43210. E-mail bauer.140{at}osu.edu
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 oxidative 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 µmol/mg of myofibrillar protein per minute; control versus AF; P<0.05). No reduction in total CK activity or myosin ATPase activity was detected. This selective reduction in MM-CK activity was associated with increased relative expression of the ß-myosin isoform (25±6 versus 63±5%ß, 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 (peroxynitrite biomarker) and protein carbonyls (hydroxyl radical biomarker; P<0.05). Patterns of these oxidative markers were distinct, which suggests discrete chemical events and differential protein vulnerabilities in vivo. MM-CK inhibition was statistically correlated to extent of nitration (P<0.01) but not to carbonyl presence.
Conclusions—— The present results provide novel evidence of oxidative damage in human AF that altered myofibrillar energetics may contribute to atrial contractile dysfunction and that protein nitration may be an important participant in this condition.
Key Words: arrythmia • creatine kinase • nitric oxide • 3-nitrotyrosine • contractility
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