Cellular and Molecular Mechanisms of Atrial Arrhythmogenesis in Patients With Paroxysmal Atrial Fibrillation
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- Niels Voigt
- From the Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (N.V., J.H., D.D.); Division of Experimental Cardiology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (N.V., D.D.); Cardiovascular Research Institute, Department of Molecular Physiology and Biophysics and Department of Medicine, Baylor College of Medicine, Houston, TX (Q.W., D.Y.C., N.L., X.H.T.W.); Department of Cardiac Surgery, Heidelberg University, Heidelberg, Germany (M.K.);...
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- Jordi Heijman
- From the Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (N.V., J.H., D.D.); Division of Experimental Cardiology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (N.V., D.D.); Cardiovascular Research Institute, Department of Molecular Physiology and Biophysics and Department of Medicine, Baylor College of Medicine, Houston, TX (Q.W., D.Y.C., N.L., X.H.T.W.); Department of Cardiac Surgery, Heidelberg University, Heidelberg, Germany (M.K.);...
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- Qiongling Wang
- From the Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (N.V., J.H., D.D.); Division of Experimental Cardiology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (N.V., D.D.); Cardiovascular Research Institute, Department of Molecular Physiology and Biophysics and Department of Medicine, Baylor College of Medicine, Houston, TX (Q.W., D.Y.C., N.L., X.H.T.W.); Department of Cardiac Surgery, Heidelberg University, Heidelberg, Germany (M.K.);...
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- David Y. Chiang
- From the Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (N.V., J.H., D.D.); Division of Experimental Cardiology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (N.V., D.D.); Cardiovascular Research Institute, Department of Molecular Physiology and Biophysics and Department of Medicine, Baylor College of Medicine, Houston, TX (Q.W., D.Y.C., N.L., X.H.T.W.); Department of Cardiac Surgery, Heidelberg University, Heidelberg, Germany (M.K.);...
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- Na Li
- From the Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (N.V., J.H., D.D.); Division of Experimental Cardiology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (N.V., D.D.); Cardiovascular Research Institute, Department of Molecular Physiology and Biophysics and Department of Medicine, Baylor College of Medicine, Houston, TX (Q.W., D.Y.C., N.L., X.H.T.W.); Department of Cardiac Surgery, Heidelberg University, Heidelberg, Germany (M.K.);...
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- Matthias Karck
- From the Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (N.V., J.H., D.D.); Division of Experimental Cardiology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (N.V., D.D.); Cardiovascular Research Institute, Department of Molecular Physiology and Biophysics and Department of Medicine, Baylor College of Medicine, Houston, TX (Q.W., D.Y.C., N.L., X.H.T.W.); Department of Cardiac Surgery, Heidelberg University, Heidelberg, Germany (M.K.);...
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- Xander H.T. Wehrens
- From the Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (N.V., J.H., D.D.); Division of Experimental Cardiology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (N.V., D.D.); Cardiovascular Research Institute, Department of Molecular Physiology and Biophysics and Department of Medicine, Baylor College of Medicine, Houston, TX (Q.W., D.Y.C., N.L., X.H.T.W.); Department of Cardiac Surgery, Heidelberg University, Heidelberg, Germany (M.K.);...
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- Stanley Nattel
- From the Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (N.V., J.H., D.D.); Division of Experimental Cardiology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (N.V., D.D.); Cardiovascular Research Institute, Department of Molecular Physiology and Biophysics and Department of Medicine, Baylor College of Medicine, Houston, TX (Q.W., D.Y.C., N.L., X.H.T.W.); Department of Cardiac Surgery, Heidelberg University, Heidelberg, Germany (M.K.);...
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- Dobromir Dobrev
- From the Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (N.V., J.H., D.D.); Division of Experimental Cardiology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (N.V., D.D.); Cardiovascular Research Institute, Department of Molecular Physiology and Biophysics and Department of Medicine, Baylor College of Medicine, Houston, TX (Q.W., D.Y.C., N.L., X.H.T.W.); Department of Cardiac Surgery, Heidelberg University, Heidelberg, Germany (M.K.);...
説明
<jats:sec> <jats:title>Background—</jats:title> <jats:p> Electrical, structural, and Ca <jats:sup>2+</jats:sup> -handling remodeling contribute to the perpetuation/progression of atrial fibrillation (AF). Recent evidence has suggested a role for spontaneous sarcoplasmic reticulum Ca <jats:sup>2+</jats:sup> -release events in long-standing persistent AF, but the occurrence and mechanisms of sarcoplasmic reticulum Ca <jats:sup>2+</jats:sup> -release events in paroxysmal AF (pAF) are unknown. </jats:p> </jats:sec> <jats:sec> <jats:title>Method and Results—</jats:title> <jats:p> Right-atrial appendages from control sinus rhythm patients or patients with pAF (last episode a median of 10–20 days preoperatively) were analyzed with simultaneous measurements of [Ca <jats:sup>2+</jats:sup> ] <jats:sub>i</jats:sub> (fluo-3-acetoxymethyl ester) and membrane currents/action potentials (patch-clamp) in isolated atrial cardiomyocytes, and Western blot. Action potential duration, L-type Ca <jats:sup>2+</jats:sup> current, and Na <jats:sup>+</jats:sup> /Ca <jats:sup>2+</jats:sup> -exchange current were unaltered in pAF, indicating the absence of AF-induced electrical remodeling. In contrast, there were increases in SR Ca <jats:sup>2+</jats:sup> leak and incidence of delayed after-depolarizations in pAF. Ca <jats:sup>2+</jats:sup> -transient amplitude and sarcoplasmic reticulum Ca <jats:sup>2+</jats:sup> load (caffeine-induced Ca <jats:sup>2+</jats:sup> -transient amplitude, integrated Na <jats:sup>+</jats:sup> /Ca <jats:sup>2+</jats:sup> -exchange current) were larger in pAF. Ca <jats:sup>2+</jats:sup> -transient decay was faster in pAF, but the decay of caffeine-induced Ca <jats:sup>2+</jats:sup> transients was unaltered, suggesting increased SERCA2a function. In agreement, phosphorylation (inactivation) of the SERCA2a-inhibitor protein phospholamban was increased in pAF. Ryanodine receptor fractional phosphorylation was unaltered in pAF, whereas ryanodine receptor expression and single-channel open probability were increased. A novel computational model of the human atrial cardiomyocyte indicated that both ryanodine receptor dysregulation and enhanced SERCA2a activity promote increased sarcoplasmic reticulum Ca <jats:sup>2+</jats:sup> leak and sarcoplasmic reticulum Ca <jats:sup>2+</jats:sup> -release events, causing delayed after-depolarizations/triggered activity in pAF. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p> Increased diastolic sarcoplasmic reticulum Ca <jats:sup>2+</jats:sup> leak and related delayed after-depolarizations/triggered activity promote cellular arrhythmogenesis in pAF patients. Biochemical, functional, and modeling studies point to a combination of increased sarcoplasmic reticulum Ca <jats:sup>2+</jats:sup> load related to phospholamban hyperphosphorylation and ryanodine receptor dysregulation as underlying mechanisms. </jats:p> </jats:sec>
収録刊行物
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- Circulation
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Circulation 129 (2), 145-156, 2014-01-14
Ovid Technologies (Wolters Kluwer Health)