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- Eleonora Grandi
- From the Department of Pharmacology, University of California, Davis, Davis, CA (E.G., D.M.B.); Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI (S.V.P., J.J.); the Division of Experimental Cardiology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany (N.V., D.D.); and the Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (A.J.W.).
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- Sandeep V. Pandit
- From the Department of Pharmacology, University of California, Davis, Davis, CA (E.G., D.M.B.); Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI (S.V.P., J.J.); the Division of Experimental Cardiology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany (N.V., D.D.); and the Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (A.J.W.).
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- Niels Voigt
- From the Department of Pharmacology, University of California, Davis, Davis, CA (E.G., D.M.B.); Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI (S.V.P., J.J.); the Division of Experimental Cardiology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany (N.V., D.D.); and the Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (A.J.W.).
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- Antony J. Workman
- From the Department of Pharmacology, University of California, Davis, Davis, CA (E.G., D.M.B.); Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI (S.V.P., J.J.); the Division of Experimental Cardiology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany (N.V., D.D.); and the Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (A.J.W.).
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- Dobromir Dobrev
- From the Department of Pharmacology, University of California, Davis, Davis, CA (E.G., D.M.B.); Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI (S.V.P., J.J.); the Division of Experimental Cardiology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany (N.V., D.D.); and the Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (A.J.W.).
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- José Jalife
- From the Department of Pharmacology, University of California, Davis, Davis, CA (E.G., D.M.B.); Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI (S.V.P., J.J.); the Division of Experimental Cardiology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany (N.V., D.D.); and the Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (A.J.W.).
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- Donald M. Bers
- From the Department of Pharmacology, University of California, Davis, Davis, CA (E.G., D.M.B.); Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI (S.V.P., J.J.); the Division of Experimental Cardiology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany (N.V., D.D.); and the Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (A.J.W.).
書誌事項
- タイトル別名
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- Sinus Rhythm and Chronic Atrial Fibrillation
説明
<jats:sec> <jats:title> <jats:underline>Rationale:</jats:underline> </jats:title> <jats:p> Understanding atrial fibrillation (AF) requires integrated understanding of ionic currents and Ca <jats:sup>2+</jats:sup> transport in remodeled human atrium, but appropriate models are limited. </jats:p> </jats:sec> <jats:sec> <jats:title> <jats:underline>Objective:</jats:underline> </jats:title> <jats:p>To study AF, we developed a new human atrial action potential (AP) model, derived from atrial experimental results and our human ventricular myocyte model.</jats:p> </jats:sec> <jats:sec> <jats:title> <jats:underline>Methods and Results:</jats:underline> </jats:title> <jats:p> Atria versus ventricles have lower I <jats:sub>K1</jats:sub> , resulting in more depolarized resting membrane potential (≈7 mV). We used higher I <jats:sub>to,fast</jats:sub> density in atrium, removed I <jats:sub>to,slow</jats:sub> , and included an atrial-specific I <jats:sub>Kur</jats:sub> . I <jats:sub>NCX</jats:sub> and I <jats:sub>NaK</jats:sub> densities were reduced in atrial versus ventricular myocytes according to experimental results. SERCA function was altered to reproduce human atrial myocyte Ca <jats:sup>2+</jats:sup> transients. To simulate chronic AF, we reduced I <jats:sub>CaL</jats:sub> , I <jats:sub>to</jats:sub> , I <jats:sub>Kur</jats:sub> and SERCA, and increased I <jats:sub>K1</jats:sub> ,I <jats:sub>Ks</jats:sub> and I <jats:sub>NCX</jats:sub> . We also investigated the link between Kv1.5 channelopathy, [Ca <jats:sup>2+</jats:sup> ] <jats:sub>i</jats:sub> , and AF. The sinus rhythm model showed a typical human atrial AP morphology. Consistent with experiments, the model showed shorter APs and reduced AP duration shortening at increasing pacing frequencies in AF or when I <jats:sub>CaL</jats:sub> was partially blocked, suggesting a crucial role of Ca <jats:sup>2+</jats:sup> and Na <jats:sup>+</jats:sup> in this effect. This also explained blunted Ca <jats:sup>2+</jats:sup> transient and rate-adaptation of [Ca <jats:sup>2+</jats:sup> ] <jats:sub>i</jats:sub> and [Na <jats:sup>+</jats:sup> ] <jats:sub>i</jats:sub> in chronic AF. Moreover, increasing [Na <jats:sup>+</jats:sup> ] <jats:sub>i</jats:sub> and altered I <jats:sub>NaK</jats:sub> and I <jats:sub>NCX</jats:sub> causes rate-dependent atrial AP shortening. Blocking I <jats:sub>Kur</jats:sub> to mimic Kv1.5 loss-of-function increased [Ca <jats:sup>2+</jats:sup> ] <jats:sub>i</jats:sub> and caused early afterdepolarizations under adrenergic stress, as observed experimentally. </jats:p> </jats:sec> <jats:sec> <jats:title> <jats:underline>Conclusions:</jats:underline> </jats:title> <jats:p> Our study provides a novel tool and insights into ionic bases of atrioventricular AP differences, and shows how Na <jats:sup>+</jats:sup> and Ca <jats:sup>2+</jats:sup> homeostases critically mediate abnormal repolarization in AF. </jats:p> </jats:sec>
収録刊行物
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- Circulation Research
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Circulation Research 109 (9), 1055-1066, 2011-10-14
Ovid Technologies (Wolters Kluwer Health)