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(Circulation. 2006;114:670-680.)
© 2006 American Heart Association, Inc.

Molecular Cardiology

Molecular Determinants of Altered Ca²⁺ Handling in Human Chronic Atrial Fibrillation

Ali El-Armouche, MD; Peter Boknik, PhD; Thomas Eschenhagen, MD; Lucie Carrier, PhD; Michael Knaut, MD; Ursula Ravens, MD; Dobromir Dobrev, MD

From the Institute of Experimental and Clinical Pharmacology and Toxicology (A.E.-A., L.C., T.E.), Medical Center Hamburg-Eppendorf, Germany; Department of Pharmacology and Toxicology, University of Münster (P.B.), Münster, Germany; INSERM U582, University Pierre et Marie Curie, Paris, France (L.C.); and Cardiovascular Center (M.K.) and Department of Pharmacology and Toxicology (U.R., D.D.), Dresden University of Technology, Dresden, Germany.

Correspondence to Dobromir Dobrev, Department of Pharmacology and Toxicology, Dresden University of Technology, Fetscherstraße 74, 01307 Dresden, Germany. E-mail dobrev{at}rcs.urz.tu-dresden.de

Received February 3, 2006; de novo received April 30, 2006; revision received June 8, 2006; accepted June 20, 2006.

Background— Abnormal Ca²⁺ handling may contribute to impaired atrial contractility and arrhythmogenesis in human chronic atrial fibrillation (cAF). Here, we assessed the phosphorylation levels of key proteins involved in altered Ca²⁺ handling and contractility in cAF patients.

Methods and Results— Total and phosphorylation levels of Ca²⁺-handling and myofilament proteins were analyzed by Western blotting in right atrial appendages of 49 patients in sinus rhythm and 52 cAF patients. We found a higher total activity of type 1 (PP1) and type 2A phosphatases in cAF, which was associated with inhomogeneous changes of protein phosphorylation in the cellular compartments, ie, lower protein kinase A (PKA) phosphorylation of myosin binding protein-C (Ser-282 site) at the thick myofilaments but preserved PKA phosphorylation of troponin I at the thin myofilaments and enhanced PKA (Ser-16 site) and Ca²⁺-calmodulin protein kinase (Thr-17 site) phosphorylation of phospholamban. PP1 activity at sarcoplasmic reticulum is controlled by inhibitor-1 (I-1), which blocks PP1 in its PKA-phosphorylated form only. In cAF, the ratio of Thr-35–phosphorylated to total I-1 was 10-fold higher, which suggests that the enhanced phosphorylation of phospholamban may result from a stronger PP1 inhibition by PKA-hyperphosphorylated (activated) I-1.

Conclusions— Altered Ca²⁺ handling in cAF is associated with impaired phosphorylation of myosin binding protein-C, which may contribute to the contractile dysfunction after cardioversion. The hyperphosphorylation of phospholamban probably results from enhanced inhibition of sarcoplasmic PP1 by hyperphosphorylated I-1 and may reinforce the leakiness of ryanodine channels in cAF. Restoration of sarcoplasmic reticulum–associated PP1 function may represent a new therapeutic option for treatment of atrial fibrillation.

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