{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T10:18:14Z","timestamp":1792750694278,"version":"4.5.0"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2014,1,14]]},"abstract":"<jats:sec>\n                    <jats:title>Background\u2014<\/jats:title>\n                    <jats:p>\n                      Electrical, structural, and Ca\n                      <jats:sup>2+<\/jats:sup>\n                      -handling remodeling contribute to the perpetuation\/progression of atrial fibrillation (AF). Recent evidence has suggested a role for spontaneous sarcoplasmic reticulum Ca\n                      <jats:sup>2+<\/jats:sup>\n                      -release events in long-standing persistent AF, but the occurrence and mechanisms of sarcoplasmic reticulum Ca\n                      <jats:sup>2+<\/jats:sup>\n                      -release events in paroxysmal AF (pAF) are unknown.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Method and Results\u2014<\/jats:title>\n                    <jats:p>\n                      Right-atrial appendages from control sinus rhythm patients or patients with pAF (last episode a median of 10\u201320 days preoperatively) were analyzed with simultaneous measurements of [Ca\n                      <jats:sup>2+<\/jats:sup>\n                      ]\n                      <jats:sub>i<\/jats:sub>\n                      (fluo-3-acetoxymethyl ester) and membrane currents\/action potentials (patch-clamp) in isolated atrial cardiomyocytes, and Western blot. Action potential duration, L-type Ca\n                      <jats:sup>2+<\/jats:sup>\n                      current, and Na\n                      <jats:sup>+<\/jats:sup>\n                      \/Ca\n                      <jats:sup>2+<\/jats:sup>\n                      -exchange current were unaltered in pAF, indicating the absence of AF-induced electrical remodeling. In contrast, there were increases in SR Ca\n                      <jats:sup>2+<\/jats:sup>\n                      leak and incidence of delayed after-depolarizations in pAF. Ca\n                      <jats:sup>2+<\/jats:sup>\n                      -transient amplitude and sarcoplasmic reticulum Ca\n                      <jats:sup>2+<\/jats:sup>\n                      load (caffeine-induced Ca\n                      <jats:sup>2+<\/jats:sup>\n                      -transient amplitude, integrated Na\n                      <jats:sup>+<\/jats:sup>\n                      \/Ca\n                      <jats:sup>2+<\/jats:sup>\n                      -exchange current) were larger in pAF. Ca\n                      <jats:sup>2+<\/jats:sup>\n                      -transient decay was faster in pAF, but the decay of caffeine-induced Ca\n                      <jats:sup>2+<\/jats:sup>\n                      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\n                      <jats:sup>2+<\/jats:sup>\n                      leak and sarcoplasmic reticulum Ca\n                      <jats:sup>2+<\/jats:sup>\n                      -release events, causing delayed after-depolarizations\/triggered activity in pAF.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\u2014<\/jats:title>\n                    <jats:p>\n                      Increased diastolic sarcoplasmic reticulum Ca\n                      <jats:sup>2+<\/jats:sup>\n                      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\n                      <jats:sup>2+<\/jats:sup>\n                      load related to phospholamban hyperphosphorylation and ryanodine receptor dysregulation as underlying mechanisms.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.113.006641","type":"journal-article","created":{"date-parts":[[2013,11,18]],"date-time":"2013-11-18T23:58:20Z","timestamp":1384819100000},"page":"145-156","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":431,"title":["Cellular and Molecular Mechanisms of Atrial Arrhythmogenesis in Patients With Paroxysmal Atrial Fibrillation"],"prefix":"10.1161","volume":"129","author":[{"given":"Niels","family":"Voigt","sequence":"first","affiliation":[{"name":"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.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordi","family":"Heijman","sequence":"additional","affiliation":[{"name":"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.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiongling","family":"Wang","sequence":"additional","affiliation":[{"name":"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.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David Y.","family":"Chiang","sequence":"additional","affiliation":[{"name":"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.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Li","sequence":"additional","affiliation":[{"name":"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.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Karck","sequence":"additional","affiliation":[{"name":"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.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xander H.T.","family":"Wehrens","sequence":"additional","affiliation":[{"name":"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.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanley","family":"Nattel","sequence":"additional","affiliation":[{"name":"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.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dobromir","family":"Dobrev","sequence":"additional","affiliation":[{"name":"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.);..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/cir.0b013e31828124ad"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cjca.2013.07.797"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ahj.2012.05.017"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/europace\/eul107"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3682"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.2217\/fca.12.78"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI46315"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.107.754564"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pcad.2005.06.002"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.92.7.1954"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.109.933036"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199809033391003"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.110.954636"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2013.06.052"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.111.067306"},{"key":"e_1_3_4_17_2","first-page":"e50235.","article-title":"Isolation of human atrial myocytes for simultaneous measurements of Ca2+ transients and membrane currents.","volume":"77","author":"Voigt N","year":"2013","unstructured":"Voigt N, Zhou XB, Dobrev D. 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