Enhanced Sarcoplasmic Reticulum Ca <sup>2+</sup> Leak and Increased Na <sup>+</sup> -Ca <sup>2+</sup> Exchanger Function Underlie Delayed Afterdepolarizations in Patients With Chronic Atrial Fibrillation
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- Niels Voigt
- From the Division of Experimental Cardiology (N.V., I.A.-T., Q.S., D.D.) and Department of Experimental and Clinical Pharmacology (T.W.), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; Department of Pharmacology and Toxicology, Dresden University of Technology, Dresden, Germany (N.V., U.R., D.D.); Department of Molecular Physiology and Biophysics, Department of Medicine, Baylor College of Medicine, Houston, TX (N.L., Q.W., W.W., X.H.T.W.); Unit of Cardiac Physiology,...
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- Na Li
- From the Division of Experimental Cardiology (N.V., I.A.-T., Q.S., D.D.) and Department of Experimental and Clinical Pharmacology (T.W.), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; Department of Pharmacology and Toxicology, Dresden University of Technology, Dresden, Germany (N.V., U.R., D.D.); Department of Molecular Physiology and Biophysics, Department of Medicine, Baylor College of Medicine, Houston, TX (N.L., Q.W., W.W., X.H.T.W.); Unit of Cardiac Physiology,...
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- Qiongling Wang
- From the Division of Experimental Cardiology (N.V., I.A.-T., Q.S., D.D.) and Department of Experimental and Clinical Pharmacology (T.W.), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; Department of Pharmacology and Toxicology, Dresden University of Technology, Dresden, Germany (N.V., U.R., D.D.); Department of Molecular Physiology and Biophysics, Department of Medicine, Baylor College of Medicine, Houston, TX (N.L., Q.W., W.W., X.H.T.W.); Unit of Cardiac Physiology,...
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- Wei Wang
- From the Division of Experimental Cardiology (N.V., I.A.-T., Q.S., D.D.) and Department of Experimental and Clinical Pharmacology (T.W.), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; Department of Pharmacology and Toxicology, Dresden University of Technology, Dresden, Germany (N.V., U.R., D.D.); Department of Molecular Physiology and Biophysics, Department of Medicine, Baylor College of Medicine, Houston, TX (N.L., Q.W., W.W., X.H.T.W.); Unit of Cardiac Physiology,...
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- Andrew W. Trafford
- From the Division of Experimental Cardiology (N.V., I.A.-T., Q.S., D.D.) and Department of Experimental and Clinical Pharmacology (T.W.), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; Department of Pharmacology and Toxicology, Dresden University of Technology, Dresden, Germany (N.V., U.R., D.D.); Department of Molecular Physiology and Biophysics, Department of Medicine, Baylor College of Medicine, Houston, TX (N.L., Q.W., W.W., X.H.T.W.); Unit of Cardiac Physiology,...
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- Issam Abu-Taha
- From the Division of Experimental Cardiology (N.V., I.A.-T., Q.S., D.D.) and Department of Experimental and Clinical Pharmacology (T.W.), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; Department of Pharmacology and Toxicology, Dresden University of Technology, Dresden, Germany (N.V., U.R., D.D.); Department of Molecular Physiology and Biophysics, Department of Medicine, Baylor College of Medicine, Houston, TX (N.L., Q.W., W.W., X.H.T.W.); Unit of Cardiac Physiology,...
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- Qiang Sun
- From the Division of Experimental Cardiology (N.V., I.A.-T., Q.S., D.D.) and Department of Experimental and Clinical Pharmacology (T.W.), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; Department of Pharmacology and Toxicology, Dresden University of Technology, Dresden, Germany (N.V., U.R., D.D.); Department of Molecular Physiology and Biophysics, Department of Medicine, Baylor College of Medicine, Houston, TX (N.L., Q.W., W.W., X.H.T.W.); Unit of Cardiac Physiology,...
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- Thomas Wieland
- From the Division of Experimental Cardiology (N.V., I.A.-T., Q.S., D.D.) and Department of Experimental and Clinical Pharmacology (T.W.), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; Department of Pharmacology and Toxicology, Dresden University of Technology, Dresden, Germany (N.V., U.R., D.D.); Department of Molecular Physiology and Biophysics, Department of Medicine, Baylor College of Medicine, Houston, TX (N.L., Q.W., W.W., X.H.T.W.); Unit of Cardiac Physiology,...
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- Ursula Ravens
- From the Division of Experimental Cardiology (N.V., I.A.-T., Q.S., D.D.) and Department of Experimental and Clinical Pharmacology (T.W.), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; Department of Pharmacology and Toxicology, Dresden University of Technology, Dresden, Germany (N.V., U.R., D.D.); Department of Molecular Physiology and Biophysics, Department of Medicine, Baylor College of Medicine, Houston, TX (N.L., Q.W., W.W., X.H.T.W.); Unit of Cardiac Physiology,...
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- Stanley Nattel
- From the Division of Experimental Cardiology (N.V., I.A.-T., Q.S., D.D.) and Department of Experimental and Clinical Pharmacology (T.W.), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; Department of Pharmacology and Toxicology, Dresden University of Technology, Dresden, Germany (N.V., U.R., D.D.); Department of Molecular Physiology and Biophysics, Department of Medicine, Baylor College of Medicine, Houston, TX (N.L., Q.W., W.W., X.H.T.W.); Unit of Cardiac Physiology,...
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- Xander H.T. Wehrens
- From the Division of Experimental Cardiology (N.V., I.A.-T., Q.S., D.D.) and Department of Experimental and Clinical Pharmacology (T.W.), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; Department of Pharmacology and Toxicology, Dresden University of Technology, Dresden, Germany (N.V., U.R., D.D.); Department of Molecular Physiology and Biophysics, Department of Medicine, Baylor College of Medicine, Houston, TX (N.L., Q.W., W.W., X.H.T.W.); Unit of Cardiac Physiology,...
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- Dobromir Dobrev
- From the Division of Experimental Cardiology (N.V., I.A.-T., Q.S., D.D.) and Department of Experimental and Clinical Pharmacology (T.W.), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; Department of Pharmacology and Toxicology, Dresden University of Technology, Dresden, Germany (N.V., U.R., D.D.); Department of Molecular Physiology and Biophysics, Department of Medicine, Baylor College of Medicine, Houston, TX (N.L., Q.W., W.W., X.H.T.W.); Unit of Cardiac Physiology,...
抄録
<jats:sec> <jats:title>Background—</jats:title> <jats:p> Delayed afterdepolarizations (DADs) carried by Na <jats:sup>+</jats:sup> -Ca <jats:sup>2+</jats:sup> -exchange current (I <jats:sub>NCX</jats:sub> ) in response to sarcoplasmic reticulum (SR) Ca <jats:sup>2+</jats:sup> leak can promote atrial fibrillation (AF). The mechanisms leading to delayed afterdepolarizations in AF patients have not been defined. </jats:p> </jats:sec> <jats:sec> <jats:title>Methods and Results—</jats:title> <jats:p> Protein levels (Western blot), membrane currents and action potentials (patch clamp), and [Ca <jats:sup>2+</jats:sup> ] <jats:sub>i</jats:sub> (Fluo-3) were measured in right atrial samples from 76 sinus rhythm (control) and 72 chronic AF (cAF) patients. Diastolic [Ca <jats:sup>2+</jats:sup> ] <jats:sub>i</jats:sub> and SR Ca <jats:sup>2+</jats:sup> content (integrated I <jats:sub>NCX</jats:sub> during caffeine-induced Ca <jats:sup>2+</jats:sup> transient) were unchanged, whereas diastolic SR Ca <jats:sup>2+</jats:sup> leak, estimated by blocking ryanodine receptors (RyR2) with tetracaine, was ≈50% higher in cAF versus control. Single-channel recordings from atrial RyR2 reconstituted into lipid bilayers revealed enhanced open probability in cAF samples, providing a molecular basis for increased SR Ca <jats:sup>2+</jats:sup> leak. Calmodulin expression (60%), Ca <jats:sup>2+</jats:sup> /calmodulin-dependent protein kinase-II (CaMKII) autophosphorylation at Thr287 (87%), and RyR2 phosphorylation at Ser2808 (protein kinase A/CaMKII site, 236%) and Ser2814 (CaMKII site, 77%) were increased in cAF. The selective CaMKII blocker KN-93 decreased SR Ca <jats:sup>2+</jats:sup> leak, the frequency of spontaneous Ca <jats:sup>2+</jats:sup> release events, and RyR2 open probability in cAF, whereas protein kinase A inhibition with H-89 was ineffective. Knock-in mice with constitutively phosphorylated RyR2 at Ser2814 showed a higher incidence of Ca <jats:sup>2+</jats:sup> sparks and increased susceptibility to pacing-induced AF compared with controls. The relationship between [Ca <jats:sup>2+</jats:sup> ] <jats:sub>i</jats:sub> and I <jats:sub>NCX</jats:sub> density revealed I <jats:sub>NCX</jats:sub> upregulation in cAF. Spontaneous Ca <jats:sup>2+</jats:sup> release events accompanied by inward I <jats:sub>NCX</jats:sub> currents and delayed afterdepolarizations/triggered activity occurred more often and the sensitivity of resting membrane voltage to elevated [Ca <jats:sup>2+</jats:sup> ] <jats:sub>i</jats:sub> (diastolic [Ca <jats:sup>2+</jats:sup> ] <jats:sub>i</jats:sub> –voltage coupling gain) was higher in cAF compared with control. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p> Enhanced SR Ca <jats:sup>2+</jats:sup> leak through CaMKII-hyperphosphorylated RyR2, in combination with larger I <jats:sub>NCX</jats:sub> for a given SR Ca <jats:sup>2+</jats:sup> release and increased diastolic [Ca <jats:sup>2+</jats:sup> ] <jats:sub>i</jats:sub> -voltage coupling gain, causes AF-promoting atrial delayed afterdepolarizations/triggered activity in cAF patients. </jats:p> </jats:sec>
収録刊行物
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- Circulation
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Circulation 125 (17), 2059-2070, 2012-05
Ovid Technologies (Wolters Kluwer Health)